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141 results on '"M, Simeone"'

1. Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities

Author: Ariane Lozac’hmeur, Tyler Danek, Qidi Yang, Mario G. Rosasco, John S. Welch, William Y. Go, Eric W. Ng, Armen Mardiros, David G. Maloney, Edward B. Garon, Kedar Kirtane, Diane M. Simeone, Julian R. Molina, Ameen A. Salahudeen, Michelle M. Stein, and J. Randolph Hecht
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.
Published: 2024
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2. The underground argon project: procurement and purification of argon for dark matter searches and beyond

Author: P. Agnes, H. O. Back, W. Bonivento, M. G. Boulay, N. Canci, M. Caravati, S. Cebrian, V. Cocco, D. Diaz Mairena, D. Franco, F. Gabriele, D. Gahan, C. Galbiati, P. Garcia Abia, A. Gendotti, T. Hessel, S. Horikawa, R. Lopez Manzano, L. Luzzi, M. Martinez, V. Pesudo, M. Razeti, A. L. Renshaw, L. Romero, A. Rubbia, R. Santorelli, M. Simeone, R. Stefanizzi, A. Steri, and S. Sulis
Subjects: underground argon, 39Ar, 42Ar, dark matter instrumentation, 0νββ-decay instrumentation, low-radioactivity technique, Physics, QC1-999
Abstract: The existence of dark matter in the universe is inferred from abundant astrophysical and cosmological observations. The Global Argon Dark Matter Collaboration (GADMC) aims to perform the searches for dark matter in the form of weakly interacting massive particles (WIMPs), whose collisions with argon nuclei would produce nuclear recoils with tens of keV energy. Argon has been considered an excellent medium for the direct detection of WIMPs as argon-based scintillation detectors can make use of pulse shape discrimination (PSD) to separate WIMP-induced nuclear recoil signals from electron recoil backgrounds with extremely high efficiency. However, argon-based direct dark matter searches must confront the presence of intrinsic 39Ar as the predominant source of electron recoil backgrounds (it is a beta-emitter with an endpoint energy of 565 keV and half-life of 269 years). Even with PSD, the 39Ar activity in atmospheric argon (AAr), mainly produced and maintained by cosmic ray-induced nuclear reactions, limits the ultimate size of argon-based detectors and restricts their ability to probe very-low-energy events. The discovery of argon from deep underground wells with significantly less 39Ar than that in AAr was an important step in the development of direct dark matter detection experiments using argon as the active target. Thanks to pioneering research and successful R&D, in 2012, the first 160 kg batch of underground argon (UAr) was extracted from a CO2 well in Cortez, Colorado. The DarkSide-50 experiment at the Gran Sasso National Laboratory (LNGS) in Italy, the first liquid argon detector ever operated with a UAr target, demonstrated a ∼ 1,400 suppression of the 39Ar activity with respect to the atmospheric argon. An even larger suppression is expected for 42Ar (another intrinsic beta-emitter with the 42K daughter isotope, also a beta-emitter) as its production is expected mainly in the upper atmosphere. Following the results of DarkSide-50, the GADMC initiated the UAr project for extraction from underground and cryogenic purification of 100 t of argon to be used as a target in the next-generation experiment DarkSide-20k. This paper contains a description of the Urania Plant in Cortez, Colorado, where UAr is extracted; the Aria Plant in Sardinia, Italy, an industrial-scale plant comprising a 350-m state-of-the-art cryogenic isotopic distillation column, designed for further purification of the extracted argon and further reduction of the isotopic abundance of 39Ar; and DArT, a facility for UAr radiopurity qualification at the Canfranc Underground Laboratory (LSC), Spain. Moreover, the high radiopurity of UAr leads to other possible applications, for instance, for those neutrinoless double-beta decay experiments using argon as shielding material or, more generally, for all those activities on argon-based detectors in high-energy physics or nuclear physics, which will be briefly discussed.
Published: 2024
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3. Measurement of isotopic separation of argon with the prototype of the cryogenic distillation plant Aria for dark matter searches

Author: E. Aaron, P. Agnes, I. Ahmad, S. Albergo, I. F. M. Albuquerque, T. Alexander, A. K. Alton, P. Amaudruz, M. Atzori Corona, M. Ave, I. Ch. Avetisov, O. Azzolini, H. O. Back, Z. Balmforth, A. Barrado, P. Barrillon, A. Basco, G. Batignani, V. Bocci, W. M. Bonivento, B. Bottino, M. G. Boulay, J. Busto, M. Cadeddu, A. Caminata, N. Canci, A. Capra, S. Caprioli, M. Caravati, N. Cargioli, M. Carlini, P. Castello, P. Cavalcante, S. Cavuoti, S. Cebrian, J. M. Cela Ruiz, S. Chashin, A. Chepurnov, E. Chyhyrynets, L. Cifarelli, D. Cintas, M. Citterio, B. Cleveland, V. Cocco, E. Conde Vilda, L. Consiglio, S. Copello, G. Covone, M. Czubak, M. D’Aniello, S. D’Auria, M. D. Da Rocha Rolo, S. Davini, S. De Cecco, G. De Guido, D. De Gruttola, S. De Pasquale, G. De Rosa, G. Dellacasa, A. V. Derbin, A. Devoto, F. Di Capua, L. Di Noto, P. Di Stefano, G. Dolganov, F. Dordei, E. Ellingwood, T. Erjavec, S. Farenzena, M. Fernandez Diaz, G. Fiorillo, P. Franchini, D. Franco, N. Funicello, F. Gabriele, D. Gahan, C. Galbiati, G. Gallina, G. Gallus, M. Garbini, P. Garcia Abia, A. Gendotti, C. Ghiano, C. Giganti, G. K. Giovanetti, V. Goicoechea Casanueva, A. Gola, G. Grauso, G. Grilli di Cortona, A. Grobov, M. Gromov, M. Guan, M. Guerzoni, M. Gulino, C. Guo, B. R. Hackett, A. L. Hallin, A. Hamer, M. Haranczyk, T. Hessel, S. Hill, S. Horikawa, F. Hubaut, J. Hucker, T. Hugues, An. Ianni, V. Ippolito, C. Jillings, S. Jois, P. Kachru, A. A. Kemp, C. L. Kendziora, M. Kimura, I. Kochanek, K. Kondo, G. Korga, S. Koulosousas, A. Kubankin, M. Kuss, M. Kuźniak, M. La Commara, M. Lai, N. Lami, E. Le Guirriec, E. Leason, A. Leoni, L. Lidey, F. Lippi, M. Lissia, L. Luzzi, O. Lychagina, N. Maccioni, O. Macfadyen, I. N. Machulin, S. Manecki, I. Manthos, L. Mapelli, A. Margotti, S. M. Mari, C. Mariani, J. Maricic, A. Marini, M. Martínez, C. J. Martoff, M. Mascia, A. Masoni, G. Matteucci, K. Mavrokoridis, C. Maxia, A. B. McDonald, A. Messina, R. Milincic, A. Mitra, A. Moharana, S. Moioli, J. Monroe, E. Moretti, M. Morrocchi, T. Mróz, V. N. Muratova, C. Muscas, P. Musico, R. Nania, M. Nessi, K. Nikolopoulos, J. Nowak, K. Olchansky, A. Oleinik, V. Oleynikov, P. Organtini, A. Ortiz de Solórzano, L. Pagani, M. Pallavicini, L. Pandola, E. Pantic, E. Paoloni, G. Paternoster, P. A. Pegoraro, K. Pelczar, L. A. Pellegrini, C. Pellegrino, V. Pesudo, S. Piacentini, L. Pietrofaccia, N. Pino, A. Pocar, D. M. Poehlmann, S. Pordes, P. Pralavorio, D. Price, F. Ragusa, Y. Ramachers, M. Razeti, A. L. Renshaw, M. Rescigno, F. Retiere, L. P. Rignanese, C. Ripoli, A. Rivetti, A. Roberts, C. Roberts, J. Rode, G. Rogers, L. Romero, M. Rossi, A. Rubbia, M. A. Sabia, G. M. Sabiu, P. Salomone, E. Sandford, S. Sanfilippo, D. Santone, R. Santorelli, C. Savarese, E. Scapparone, G. Schillaci, F. Schukman, G. Scioli, M. Simeone, P. Skensved, M. D. Skorokhvatov, O. Smirnov, T. Smirnova, B. Smith, F. Spadoni, M. Spangenberg, R. Stefanizzi, A. Steri, V. Stornelli, S. Stracka, M. Stringer, S. Sulis, A. Sung, Y. Suvorov, A. M. Szelc, R. Tartaglia, A. Taylor, J. Taylor, S. Tedesco, G. Testera, K. Thieme, T. N. Thorpe, A. Tonazzo, A. Tricomi, E. V. Unzhakov, T. Vallivilayil John, M. Van Uffelen, T. Viant, S. Viel, R. B. Vogelaar, J. Vossebeld, M. Wada, M. B. Walczak, H. Wang, Y. Wang, S. Westerdale, L. Williams, I. Wingerter-Seez, R. Wojaczyński, Ma. M. Wojcik, T. Wright, Y. Xie, C. Yang, A. Zabihi, P. Zakhary, A. Zani, A. Zichichi, G. Zuzel, M. P. Zykova, and DarkSide-20k Collaboration
Subjects: Astrophysics, QB460-466, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract: Abstract The Aria cryogenic distillation plant, located in Sardinia, Italy, is a key component of the DarkSide-20k experimental program for WIMP dark matter searches at the INFN Laboratori Nazionali del Gran Sasso, Italy. Aria is designed to purify the argon, extracted from underground wells in Colorado, USA, and used as the DarkSide-20k target material, to detector-grade quality. In this paper, we report the first measurement of argon isotopic separation by distillation with the 26 m tall Aria prototype. We discuss the measurement of the operating parameters of the column and the observation of the simultaneous separation of the three stable argon isotopes: $${}^{36}\hbox {Ar}$$ 36 Ar , $${}^{38}\textrm{Ar}$$ 38 Ar , and $${}^{40}\textrm{Ar}$$ 40 Ar . We also provide a detailed comparison of the experimental results with commercial process simulation software. This measurement of isotopic separation of argon is a significant achievement for the project, building on the success of the initial demonstration of isotopic separation of nitrogen using the same equipment in 2019.
Published: 2023
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4. 634 EVEREST-1: A seamless phase 1/2 study of CEA logic-gated Tmod CAR T-cell therapy (A2B530) in patients with solid tumors associated with CEA expression also exhibiting HLA loss of heterozygosity (LOH)

Author: Sarah Nikiforow, Yi Lin, Marcela Maus, Armen Mardiros, Frederick L Locke, Scott Kopetz, Matthew Frigault, David Maloney, Jeffrey Ward, Jennifer Specht, Edward Garon, Diane M Simeone, John Welch, Kedar Kirtane, Marwan Fakih, Julian Molina, Kirstin Liechty, Ariane Lozac’hmeur, J Randolph Hecht, Caleb Smith, Salman R Punekar, Theodore Welling, M Pia Morelli, Patrick M Grierson, Sandip P Patel, Wen-Kai Weng, Tomislav Dragovich, Judy Vong, William Y Go, and Eric W Ng
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2023
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5. 636 BASECAMP-1: A master prescreening study to identify patients with high-risk or metastatic solid tumors with HLA loss of heterozygosity (LOH) in preparation for Tmod CAR T-cell therapy trials

Author: Marcela Maus, Caron Jacobson, Frederick L Locke, Oliver Dorigo, David Maloney, Jennifer Specht, Saurabh Dahiya, Edward Garon, Diane M Simeone, John Welch, Kedar Kirtane, Marwan Fakih, Julian Molina, Ariane Lozac’hmeur, J Randolph Hecht, Jong Chul Park, Caleb Smith, Theodore Welling, M Pia Morelli, Patrick M Grierson, Tomislav Dragovich, William Y Go, Eric W Ng, Peter Vu, Jessica Tebbets, and Gayanie Ong
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2023
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6. Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting

Author: Jessica N. Everett, Shenin A. Sanoba, Xiaohong Jing, Cody Stender, Madeleine Schmitter, Ariele Baptiste, Jennifer Chun, Emily A. Kawaler, Lauren G. Khanna, Seth A. Gross, Tamas A. Gonda, Nina Beri, Paul E. Oberstein, and Diane M. Simeone
Subjects: family history, genetic counseling, genetic testing, germline variants, multidisciplinary care, pancreatic cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment‐ and survival‐related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high‐risk individuals (HRI) could: (1) improve compliance with guideline‐based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. Methods Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC‐associated genes at minimum. Results Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC‐related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non‐MDPC PDAC patients completed genetic testing (p
Published: 2023
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7. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Author: Gregor Werba, Daniel Weissinger, Emily A. Kawaler, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Lidong Wang, Heather B. Lim, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, and Diane M. Simeone
Subjects: Science
Abstract: Abstract The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
Published: 2023
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8. POLQ inhibition elicits an immune response in homologous recombination–deficient pancreatic adenocarcinoma via cGAS/STING signaling

Author: Grace Oh, Annie Wang, Lidong Wang, Jiufeng Li, Gregor Werba, Daniel Weissinger, Ende Zhao, Surajit Dhara, Rosmel E. Hernandez, Amanda Ackermann, Sarina Porcella, Despoina Kalfakakou, Igor Dolgalev, Emily Kawaler, Talia Golan, Theodore H. Welling, Agnel Sfeir, and Diane M. Simeone
Subjects: Cell biology, Medicine
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination–repair (HR-repair) proteins in 20%–25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.
Published: 2023
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9. Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies

Author: Shanshan Wan, Ende Zhao, Daniel Freeman, Daniel Weissinger, Benjamin A. Krantz, Gregor Werba, Lauren G. Khanna, Despina Siolas, Paul E. Oberstein, Pratip K. Chattopadhyay, Diane M. Simeone, and Theodore H. Welling
Subjects: pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, immune oncology, tumor immunity, T cell biology, Immunologic diseases. Allergy, RC581-607
Published: 2023
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10. Cyst fluid metabolites distinguish malignant from benign pancreatic cysts

Author: Jiaqi Shi, Zhujun Yi, Lin Jin, Lili Zhao, Alexander Raskind, Larisa Yeomans, Zeribe C. Nwosu, Diane M. Simeone, Costas A. Lyssiotis, Kathleen A. Stringer, and Richard S. Kwon
Subjects: Metabolite, Butyrylcarnitine, Diagnosis, Mucinous cyst, 5-oxoproline, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: OBJECTIVES: Current standard of care imaging, cytology, or cystic fluid analysis cannot reliably differentiate malignant from benign pancreatic cystic neoplasms. This study sought to determine if the metabolic profile of cystic fluid could distinguish benign and malignant lesions, as well as mucinous and non-mucinous lesions. Methods: Metabolic profiling by untargeted mass spectrometry and quantitative nuclear magnetic resonance was performed in 24 pancreatic cyst fluid from surgically resected samples with pathological diagnoses and clinicopathological correlation. Results: (Iso)-butyrylcarnitine distinguished malignant from benign pancreatic cysts, with a diagnostic accuracy of 89%. (Iso)-butyrylcarnitine was 28-fold more abundant in malignant cyst fluid compared with benign cyst fluid (P=.048). Furthermore, 5-oxoproline (P=.01) differentiated mucinous from non-mucinous cysts with a diagnostic accuracy of 90%, better than glucose (82% accuracy), a previously described metabolite that distinguishes mucinous from non-mucinous cysts. Combined analysis of glucose and 5-oxoproline did not improve the diagnostic accuracy. In comparison, standard of care cyst fluid carcinoembryonic antigen (CEA) and cytology had a diagnostic accuracy of 40% and 60% respectively for mucinous cysts. (Iso)-butyrylcarnitine and 5-oxoproline correlated with cyst fluid CEA levels (P 3 cm, ≥ 1 high-risk features, cyst fluid CEA, and cytology are 38%, 75%, 80%, and 75%, respectively. Conclusions: (Iso)-butyrylcarnitine has potential clinical application for accurately distinguishing malignant from benign pancreatic cysts, and 5-oxoproline for distinguishing mucinous from non-mucinous cysts.
Published: 2021
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11. Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies

Author: Shanshan Wan, Ende Zhao, Daniel Freeman, Daniel Weissinger, Benjamin A. Krantz, Gregor Werba, Lauren G. Khanna, Despina Siolas, Paul E. Oberstein, Pratip K. Chattopadhyay, Diane M. Simeone, and Theodore H. Welling
Subjects: pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, immune oncology, tumor immunity, T cell biology, Immunologic diseases. Allergy, RC581-607
Abstract: Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell phenotypic states, particularly in terms of immune checkpoint receptor expression, in the tumor microenvironment of HPB patients utilizing novel, multiparameter flow cytometry and bioinformatics analysis. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, with simultaneous expression of multiple co-inhibitory checkpoint receptors. Terminally differentiated T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that might confer restored activation in response to immune checkpoint therapies. Further, T-cell activation state and checkpoint expression did not change robustly in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.
Published: 2023
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12. Gallium-68-labeled fibroblast activation protein inhibitor-46 PET in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma: A phase 2, multicenter, single arm, open label non-randomized study protocol

Author: Aashna Karbhari, Sherly Mosessian, Kamaxi H. Trivedi, Frank Valla, Mark Jacobson, Mark J. Truty, Nandakumar G. Patnam, Diane M. Simeone, Elcin Zan, Tracy Brennan, Hongli Chen, Phillip H. Kuo, Ken Herrmann, and Ajit H. Goenka
Subjects: Medicine, Science
Published: 2023

13. Impact of changing guidelines on genetic testing and surveillance recommendations in a contemporary cohort of breast cancer survivors with family history of pancreatic cancer

Author: Annie Wang, Jessica N. Everett, Jennifer Chun, Cindy Cen, Diane M. Simeone, and Freya Schnabel
Subjects: Medicine, Science
Abstract: Abstract Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010 and 2018 in the NYU Langone Health Breast Cancer Database. Among 3334 BC patients, 232 (7%) had a positive FHPC. BC patients with FHPC were 1.68 times more likely to have undergone genetic testing (p
Published: 2021
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14. Evaluating Differences in Whole Blood, Serum, and Urine Screening Tests for Zika Virus, Puerto Rico, USA, 2016

Author: Asher Y. Rosinger, Samantha M. Olson, Sascha R. Ellington, Janice Perez-Padilla, Regina M. Simeone, Caitlin S. Pedati, Betsy A. Schroeder, Gilberto A. Santiago, Freddy A. Medina, Jorge L. Muñoz-Jordán, Laura E. Adams, Romeo R. Galang, Miguel Valencia-Prado, Sonia Bakkour, Candimar Colón, Mary Goodwin, Dana Meaney-Delman, Jennifer S. Read, Lyle R. Petersen, Denise J. Jamieson, Carmen C. Deseda, Margaret A. Honein, Brenda Rivera-García, and Carrie K. Shapiro-Mendoza
Subjects: Zika virus, PCR, pregnancy, whole blood, Puerto Rico, outbreak, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015–2016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens.
Published: 2021
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15. Author Correction: Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Author: Gregor Werba, Daniel Weissinger, Emily A. Kawaler, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Lidong Wang, Heather B. Lim, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, and Diane M. Simeone
Subjects: Science
Published: 2023
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16. Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis

Author: Yong Xia, Yan Liu, Chao Yang, Diane M. Simeone, Tung-Tien Sun, David J. DeGraff, Moon-shong Tang, Yingkai Zhang, and Xue-Ru Wu
Subjects: Science
Abstract: The human chromosome locus 9p21.3 is a tumour suppressor hub which encodes three CDK inhibitors, p15INK4B, p14ARF and p16INK4A. Here, the authors show that p15INK4B inhibits the cell cycle and glycolysis in a murine model of HRas + ‐mediated urothelial carcinoma and has a more relevant role as a tumour suppressor than its neighbouring p16INK4A.
Published: 2021
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17. Separating $${^{39}\hbox {Ar}}$$ 39 Ar from $${^{40}\hbox {Ar}}$$ 40 Ar by cryogenic distillation with Aria for dark-matter searches

Author: P. Agnes, S. Albergo, I. F. M. Albuquerque, T. Alexander, A. Alici, A. K. Alton, P. Amaudruz, M. Arba, P. Arpaia, S. Arcelli, M. Ave, I. Ch. Avetissov, R. I. Avetisov, O. Azzolini, H. O. Back, Z. Balmforth, V. Barbarian, A. Barrado Olmedo, P. Barrillon, A. Basco, G. Batignani, A. Bondar, W. M. Bonivento, E. Borisova, B. Bottino, M. G. Boulay, G. Buccino, S. Bussino, J. Busto, A. Buzulutskov, M. Cadeddu, M. Cadoni, A. Caminata, E. V. Canesi, N. Canci, G. Cappello, M. Caravati, M. Cárdenas-Montes, N. Cargioli, M. Carlini, F. Carnesecchi, P. Castello, A. Castellani, S. Catalanotti, V. Cataudella, P. Cavalcante, S. Cavuoti, S. Cebrian, J. M. Cela Ruiz, B. Celano, S. Chashin, A. Chepurnov, C. Cicalò, L. Cifarelli, D. Cintas, F. Coccetti, V. Cocco, M. Colocci, E. Conde Vilda, L. Consiglio, S. Copello, J. Corning, G. Covone, P. Czudak, M. D’Aniello, S. D’Auria, M. D. Da Rocha Rolo, O. Dadoun, M. Daniel, S. Davini, A. De Candia, S. De Cecco, A. De Falco, G. De Filippis, D. De Gruttola, G. De Guido, G. De Rosa, M. Della Valle, G. Dellacasa, S. De Pasquale, A. V. Derbin, A. Devoto, L. Di Noto, F. Di Eusanio, C. Dionisi, P. Di Stefano, G. Dolganov, D. Dongiovanni, F. Dordei, M. Downing, T. Erjavec, S. Falciano, S. Farenzena, M. Fernandez Diaz, C. Filip, G. Fiorillo, A. Franceschi, D. Franco, E. Frolov, N. Funicello, F. Gabriele, C. Galbiati, M. Garbini, P. Garcia Abia, A. Gendotti, C. Ghiano, R. A. Giampaolo, C. Giganti, M. A. Giorgi, G. K. Giovanetti, M. L. Gligan, V. Goicoechea Casanueva, A. Gola, A. M. Goretti, R. Graciani Diaz, G. Y. Grigoriev, A. Grobov, M. Gromov, M. Guan, M. Guerzoni, M. Guetti, M. Gulino, C. Guo, B. R. Hackett, A. Hallin, M. Haranczyk, S. Hill, S. Horikawa, F. Hubaut, T. Hugues, E. V. Hungerford, An. Ianni, V. Ippolito, C. C. James, C. Jillings, P. Kachru, A. A. Kemp, C. L. Kendziora, G. Keppel, A. V. Khomyakov, A. Kish, I. Kochanek, K. Kondo, G. Korga, A. Kubankin, R. Kugathasan, M. Kuss, M. Kuźniak, M. La Commara, L. La Delfa, D. La Grasta, M. Lai, N. Lami, S. Langrock, M. Leyton, X. Li, L. Lidey, F. Lippi, M. Lissia, G. Longo, N. Maccioni, I. N. Machulin, L. Mapelli, A. Marasciulli, A. Margotti, S. M. Mari, J. Maricic, M. Marinelli, M. Martínez, A. D. Martinez Rojas, A. Martini, M. Mascia, M. Masetto, A. Masoni, A. Mazzi, A. B. McDonald, J. Mclaughlin, A. Messina, P. D. Meyers, T. Miletic, R. Milincic, R. Miola, A. Moggi, A. Moharana, S. Moioli, J. Monroe, S. Morisi, M. Morrocchi, E. N. Mozhevitina, T. Mróz, V. N. Muratova, A. Murenu, C. Muscas, L. Musenich, P. Musico, R. Nania, T. Napolitano, A. Navrer Agasson, M. Nessi, I. Nikulin, J. Nowak, A. Oleinik, V. Oleynikov, L. Pagani, M. Pallavicini, S. Palmas, L. Pandola, E. Pantic, E. Paoloni, G. Paternoster, P. A. Pegoraro, L. A. Pellegrini, C. Pellegrino, K. Pelczar, F. Perotti, V. Pesudo, E. Picciau, F. Pietropaolo, T. Pinna, A. Pocar, P. Podda, D. M. Poehlmann, S. Pordes, S. S. Poudel, P. Pralavorio, D. Price, F. Raffaelli, F. Ragusa, A. Ramirez, M. Razeti, A. Razeto, A. L. Renshaw, S. Rescia, M. Rescigno, F. Resnati, F. Retiere, L. P. Rignanese, C. Ripoli, A. Rivetti, J. Rode, L. Romero, M. Rossi, A. Rubbia, M. Rucaj, G. M. Sabiu, P. Salatino, O. Samoylov, E. Sánchez García, E. Sandford, S. Sanfilippo, V. A. Sangiorgio, V. Santacroce, D. Santone, R. Santorelli, A. Santucci, C. Savarese, E. Scapparone, B. Schlitzer, G. Scioli, D. A. Semenov, B. Shaw, A. Shchagin, A. Sheshukov, M. Simeone, P. Skensved, M. D. Skorokhvatov, O. Smirnov, B. Smith, A. Sokolov, R. Stefanizzi, A. Steri, S. Stracka, V. Strickland, M. Stringer, S. Sulis, Y. Suvorov, A. M. Szelc, J. Z. Szucs-Balazs, R. Tartaglia, G. Testera, T. N. Thorpe, A. Tonazzo, S. Torres-Lara, S. Tosti, A. Tricomi, M. Tuveri, E. V. Unzhakov, G. Usai, T. Vallivilayil John, S. Vescovi, T. Viant, S. Viel, A. Vishneva, R. B. Vogelaar, M. Wada, H. Wang, Y. Wang, S. Westerdale, R. J. Wheadon, L. Williams, Ma. M.Wojcik, Ma. Wojcik, X. Xiao, C. Yang, A. Zani, F. Zenobio, A. Zichichi, G. Zuzel, M. P. Zykova, and DarkSide-20k Collaboration
Subjects: Astrophysics, QB460-466, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract: Abstract Aria is a plant hosting a $${350}\,\hbox {m}$$ 350 m cryogenic isotopic distillation column, the tallest ever built, which is being installed in a mine shaft at Carbosulcis S.p.A., Nuraxi-Figus (SU), Italy. Aria is one of the pillars of the argon dark-matter search experimental program, lead by the Global Argon Dark Matter Collaboration. It was designed to reduce the isotopic abundance of $${^{39}\hbox {Ar}}$$ 39 Ar in argon extracted from underground sources, called Underground Argon (UAr), which is used for dark-matter searches. Indeed, $${^{39}\hbox {Ar}}$$ 39 Ar is a $$\beta $$ β -emitter of cosmogenic origin, whose activity poses background and pile-up concerns in the detectors. In this paper, we discuss the requirements, design, construction, tests, and projected performance of the plant for the isotopic cryogenic distillation of argon. We also present the successful results of the isotopic cryogenic distillation of nitrogen with a prototype plant.
Published: 2021
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18. SiPM-matrix readout of two-phase argon detectors using electroluminescence in the visible and near infrared range

Author: C. E. Aalseth, S. Abdelhakim, P. Agnes, R. Ajaj, I. F. M. Albuquerque, T. Alexander, A. Alici, A. K. Alton, P. Amaudruz, F. Ameli, J. Anstey, P. Antonioli, M. Arba, S. Arcelli, R. Ardito, I. J. Arnquist, P. Arpaia, D. M. Asner, A. Asunskis, M. Ave, H. O. Back, V. Barbaryan, A. Barrado Olmedo, G. Batignani, M. G. Bisogni, V. Bocci, A. Bondar, G. Bonfini, W. Bonivento, E. Borisova, B. Bottino, M. G. Boulay, R. Bunker, S. Bussino, A. Buzulutskov, M. Cadeddu, M. Cadoni, A. Caminata, N. Canci, A. Candela, C. Cantini, M. Caravati, M. Cariello, F. Carnesecchi, A. Castellani, P. Castello, P. Cavalcante, D. Cavazza, S. Cavuoti, S. Cebrian, J. M. Cela Ruiz, B. Celano, R. Cereseto, S. Chashin, W. Cheng, A. Chepurnov, C. Cicalò, L. Cifarelli, M. Citterio, F. Coccetti, V. Cocco, M. Colocci, E. Conde Vilda, L. Consiglio, F. Cossio, G. Covone, P. Crivelli, I. D’Antone, M. D’Incecco, M. D. Da Rocha Rolo, O. Dadoun, M. Daniel, S. Davini, S. De Cecco, M. De Deo, A. De Falco, D. De Gruttola, G. De Guido, G. De Rosa, G. Dellacasa, P. Demontis, S. De Pasquale, A. V. Derbin, A. Devoto, F. Di Eusanio, L. Di Noto, G. Di Pietro, P. Di Stefano, C. Dionisi, G. Dolganov, F. Dordei, M. Downing, F. Edalatfar, A. Empl, M. Fernandez Diaz, C. Filip, G. Fiorillo, K. Fomenko, A. Franceschi, D. Franco, E. Frolov, G. E. Froudakis, N. Funicello, F. Gabriele, A. Gabrieli, C. Galbiati, M. Garbini, P. Garcia Abia, D. Gascón Fora, A. Gendotti, C. Ghiano, A. Ghisi, P. Giampa, R. A. Giampaolo, C. Giganti, M. A. Giorgi, G. K. Giovanetti, M. L. Gligan, O. Gorchakov, M. Grab, R. Graciani Diaz, M. Grassi, J. W. Grate, A. Grobov, M. Gromov, M. Guan, M. B. B. Guerra, M. Guerzoni, M. Gulino, R. K. Haaland, B. R. Hackett, A. Hallin, M. Haranczyk, B. Harrop, E. W. Hoppe, S. Horikawa, B. Hosseini, F. Hubaut, P. Humble, E. V. Hungerford, An. Ianni, A. Ilyasov, V. Ippolito, C. Jillings, K. Keeter, C. L. Kendziora, I. Kochanek, K. Kondo, G. Kopp, D. Korablev, G. Korga, A. Kubankin, R. Kugathasan, M. Kuss, M. La Commara, L. La Delfa, M. Lai, M. Lebois, B. Lehnert, N. Levashko, X. Li, Q. Liqiang, M. Lissia, G. U. Lodi, G. Longo, R. Lussana, L. Luzzi, A. A. Machado, I. N. Machulin, A. Mandarano, S. Manecki, L. Mapelli, A. Margotti, S. M. Mari, M. Mariani, J. Maricic, M. Marinelli, D. Marras, M. Martínez, A. D. Martinez Rojas, M. Mascia, J. Mason, A. Masoni, A. B. McDonald, A. Messina, T. Miletic, R. Milincic, A. Moggi, S. Moioli, J. Monroe, M. Morrocchi, T. Mroz, W. Mu, V. N. Muratova, S. Murphy, C. Muscas, P. Musico, R. Nania, T. Napolitano, A. Navrer Agasson, M. Nessi, I. Nikulin, V. Nosov, J. A. Nowak, A. Oleinik, V. Oleynikov, M. Orsini, F. Ortica, L. Pagani, M. Pallavicini, S. Palmas, L. Pandola, E. Pantic, E. Paoloni, F. Pazzona, S. Peeters, P. A. Pegoraro, K. Pelczar, L. A. Pellegrini, C. Pellegrino, N. Pelliccia, F. Perotti, V. Pesudo, E. Picciau, F. Pietropaolo, A. Pocar, T. R. Pollmann, D. Portaluppi, S. S. Poudel, P. Pralavorio, D. Price, B. Radics, F. Raffaelli, F. Ragusa, M. Razeti, C. Regenfus, A. L. Renshaw, S. Rescia, M. Rescigno, F. Retiere, L. P. Rignanese, C. Ripoli, A. Rivetti, J. Rode, A. Romani, L. Romero, N. Rossi, A. Rubbia, P. Sala, P. Salatino, O. Samoylov, E. Sánchez García, E. Sandford, S. Sanfilippo, M. Sant, D. Santone, R. Santorelli, C. Savarese, E. Scapparone, B. Schlitzer, G. Scioli, E. Segreto, A. Seifert, D. A. Semenov, A. Shchagin, A. Sheshukov, S. Siddhanta, M. Simeone, P. N. Singh, P. Skensved, M. D. Skorokhvatov, O. Smirnov, G. Sobrero, A. Sokolov, A. Sotnikov, R. Stainforth, A. Steri, S. Stracka, V. Strickland, G. B. Suffritti, S. Sulis, Y. Suvorov, A. M. Szelc, R. Tartaglia, G. Testera, T. Thorpe, A. Tonazzo, A. Tosi, M. Tuveri, E. V. Unzhakov, G. Usai, A. Vacca, E. Vázquez-Jáuregui, T. Viant, S. Viel, F. Villa, A. Vishneva, R. B. Vogelaar, J. Wahl, J. J. Walding, H. Wang, Y. Wang, S. Westerdale, R. J. Wheadon, R. Williams, J. Wilson, Ma. M. Wojcik, Ma. Wojcik, S. Wu, X. Xiao, C. Yang, Z. Ye, M. Zuffa, G. Zuzel, and The DarkSide-20k collaboration
Subjects: Astrophysics, QB460-466, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract: Abstract Proportional electroluminescence (EL) in noble gases is used in two-phase detectors for dark matter searches to record (in the gas phase) the ionization signal induced by particle scattering in the liquid phase. The “standard” EL mechanism is considered to be due to noble gas excimer emission in the vacuum ultraviolet (VUV). In addition, there are two alternative mechanisms, producing light in the visible and near infrared (NIR) ranges. The first is due to bremsstrahlung of electrons scattered on neutral atoms (“neutral bremsstrahlung”, NBrS). The second, responsible for electron avalanche scintillation in the NIR at higher electric fields, is due to transitions between excited atomic states. In this work, we have for the first time demonstrated two alternative techniques of the optical readout of two-phase argon detectors, in the visible and NIR range, using a silicon photomultiplier matrix and electroluminescence due to either neutral bremsstrahlung or avalanche scintillation. The amplitude yield and position resolution were measured for these readout techniques, which allowed to assess the detection threshold for electron and nuclear recoils in two-phase argon detectors for dark matter searches. To the best of our knowledge, this is the first practical application of the NBrS effect in detection science.
Published: 2021
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19. Proteome heterogeneity and malignancy detection in pancreatic cyst fluids

Author: Sheng Pan, Randall E. Brand, Lisa A. Lai, David W. Dawson, Timothy R. Donahue, Stephen Kim, Natalia I. Khalaf, Mohamed O. Othman, William E. Fisher, Mary P. Bronner, Diane M. Simeone, Teresa A. Brentnall, and Ru Chen
Subjects: Medicine (General), R5-920
Published: 2021
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20. A pan-cancer organoid platform for precision medicine

Author: Brian M. Larsen, Madhavi Kannan, Lee F. Langer, Benjamin D. Leibowitz, Aicha Bentaieb, Andrea Cancino, Igor Dolgalev, Bridgette E. Drummond, Jonathan R. Dry, Chi-Sing Ho, Gaurav Khullar, Benjamin A. Krantz, Brandon Mapes, Kelly E. McKinnon, Jessica Metti, Jason F. Perera, Tim A. Rand, Veronica Sanchez-Freire, Jenna M. Shaxted, Michelle M. Stein, Michael A. Streit, Yi-Hung Carol Tan, Yilin Zhang, Ende Zhao, Jagadish Venkataraman, Martin C. Stumpe, Jeffrey A. Borgia, Ashiq Masood, Daniel V.T. Catenacci, Jeremy V. Mathews, Demirkan B. Gursel, Jian-Jun Wei, Theodore H. Welling, Diane M. Simeone, Kevin P. White, Aly A. Khan, Catherine Igartua, and Ameen A. Salahudeen
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.
Published: 2021
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21. Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth

Author: Anupama Pal, Michele Dziubinski, Marina Pasca Di Magliano, Diane M. Simeone, Scott Owens, Dafydd Thomas, Luke Peterson, Harish Potu, Moshe Talpaz, and Nicholas J. Donato
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2) and four spontaneously immortalized human pancreatic patient-derived tumor (PDX) cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041) and doxycycline-inducible (4668) KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models.
Published: 2018
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22. Projecting Month of Birth for At-Risk Infants after Zika Virus Disease Outbreaks

Author: Jennita Reefhuis, Suzanne M. Gilboa, Michael A. Johansson, Diana Valencia, Regina M. Simeone, Susan L. Hills, Kara Polen, Denise J. Jamieson, Lyle R. Petersen, and Margaret A. Honein
Subjects: Zika virus, ZIKAV, pregnancy, microcephaly, birth defects, flavivirus, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: The marked increase in infants born with microcephaly in Brazil after a 2015 outbreak of Zika virus (Zika virus) disease suggests an association between maternal Zika virus infection and congenital microcephaly. To project the timing of delivery of infants born to mothers infected during early pregnancy in 1 city in Bahia State, Brazil, we incorporated data on reported Zika virus disease cases and microcephaly cases into a graphical schematic of weekly birth cohorts. We projected that these births would occur through February 2016. Applying similar projections to a hypothetical location at which Zika virus transmission started in November, we projected that full-term infants at risk for Zika virus infection would be born during April–September 2016. We also developed a modifiable spreadsheet tool that public health officials and researchers can use for their countries to plan for deliveries of infants to women who were infected with Zika virus during different pregnancy trimesters.
Published: 2016
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23. HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties

Author: Ethan V Abel, Masashi Goto, Brian Magnuson, Saji Abraham, Nikita Ramanathan, Emily Hotaling, Anthony A Alaniz, Chandan Kumar-Sinha, Michele L Dziubinski, Sumithra Urs, Lidong Wang, Jiaqi Shi, Meghna Waghray, Mats Ljungman, Howard C Crawford, and Diane M Simeone
Subjects: pancreatic cancer stem cells, pancreatic ductal adenocarcinoma, HNF1A, OCT4, POU5F1, patient survival, Medicine, Science, Biology (General), QH301-705.5
Abstract: The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove pancreatic ductal adenocarcinoma (PDA) cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in PDA.
Published: 2018
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24. Mucin acts as a nutrient source and a signal for the differential expression of genes coding for cellular processes and virulence factors in Acinetobacter baumannii.

Author: Emily J Ohneck, Brock A Arivett, Steven E Fiester, Cecily R Wood, Maeva L Metz, Gabriella M Simeone, and Luis A Actis
Subjects: Medicine, Science
Abstract: The capacity of Acinetobacter baumannii to persist and cause infections depends on its interaction with abiotic and biotic surfaces, including those found on medical devices and host mucosal surfaces. However, the extracellular stimuli affecting these interactions are poorly understood. Based on our previous observations, we hypothesized that mucin, a glycoprotein secreted by lung epithelial cells, particularly during respiratory infections, significantly alters A. baumannii's physiology and its interaction with the surrounding environment. Biofilm, virulence and growth assays showed that mucin enhances the interaction of A. baumannii ATCC 19606T with abiotic and biotic surfaces and its cytolytic activity against epithelial cells while serving as a nutrient source. The global effect of mucin on the physiology and virulence of this pathogen is supported by RNA-Seq data showing that its presence in a low nutrient medium results in the differential transcription of 427 predicted protein-coding genes. The reduced expression of ion acquisition genes and the increased transcription of genes coding for energy production together with the detection of mucin degradation indicate that this host glycoprotein is a nutrient source. The increased expression of genes coding for adherence and biofilm biogenesis on abiotic and biotic surfaces, the degradation of phenylacetic acid and the production of an active type VI secretion system further supports the role mucin plays in virulence. Taken together, our observations indicate that A. baumannii recognizes mucin as an environmental signal, which triggers a response cascade that allows this pathogen to acquire critical nutrients and promotes host-pathogen interactions that play a role in the pathogenesis of bacterial infections.
Published: 2018
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25. DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells

Author: Jiheng Xu, Rui Yang, Jingxia Li, Lidong Wang, Mitchell Cohen, Diane M. Simeone, Max Costa, and Xue-Ru Wu
Subjects: Cancer Research, Oncology, urothelial carcinoma, muscle-invasive, stemness, SNHG1, Rac1, DNMT3A
Abstract: The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3′-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients.
Published: 2022
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26. A Pilot Study of Diffusion-Weighted MRI in Patients Undergoing Neoadjuvant Chemoradiation for Pancreatic Cancer

Author: Kyle C. Cuneo, Thomas L. Chenevert, Edgar Ben-Josef, Mary U. Feng, Joel K. Greenson, Hero K. Hussain, Diane M. Simeone, Matthew J. Schipper, Michelle A. Anderson, Mark M. Zalupski, Mahmoud Al-Hawary, Craig J. Galban, Alnawaz Rehemtulla, Felix Y. Feng, Theodore S. Lawrence, and Brian D. Ross
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: PURPOSE: In the current study we examined the ability of diffusion MRI (dMRI) to predict pathologic response in pancreatic cancer patients receiving neoadjuvant chemoradiation. METHODS: We performed a prospective pilot study of dMRI in patients with resectable pancreatic cancer. Patients underwent dMRI prior to neoadjuvant chemoradiation. Surgical specimens were graded according to the percent tumor cell destruction. Apparent diffusion coefficient (ADC) maps were used to generate whole-tumor derived ADC histogram distributions and mean ADC values. The primary objective of the study was to correlate ADC parameters with pathologic and CT response. RESULTS: Ten of the 12 patients enrolled on the study completed chemoradiation and had surgery. Three were found to be unresectable at the time of surgery and no specimen was obtained. Out of the 7 patients who underwent pancreaticoduodenectomy, 3 had a grade III histopathologic response (>90% tumor cell destruction), 2 had a grade IIB response (51% to 90% tumor cell destruction), 1 had a grade IIA response (11% to 50% tumor cell destruction), and 1 had a grade I response (>90% viable tumor). Median survival for patients with a grade III response, grade I-II response, and unresectable disease were 25.6, 18.7, and 6.1 months, respectively. There was a significant correlation between pre-treatment mean tumor ADC values and the amount of tumor cell destruction after chemoradiation with a Pearson correlation coefficient of 0.94 (P = .001). Mean pre-treatment ADC was 161 × 10−5 mm2/s (n = 3) in responding patients (>90% tumor cell destruction) compared to 125 × 10−5 mm2/s (n = 4) in non-responding patients (>10% viable tumor). CT imaging showed no significant change in tumor size in responders or non-responders. CONCLUSIONS: dMRI may be useful to predict response to chemoradiation in pancreatic cancer. In our study, tumors with a low ADC mean value at baseline responded poorly to standard chemoradiation and would be candidates for intensified therapy.
Published: 2014
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27. Sensitization of Pancreatic Cancer Stem Cells to Gemcitabine by Chk1 Inhibition

Author: Venkatasubbaiah A. Venkatesha, Leslie A. Parsels, Joshua D. Parsels, Lili Zhao, Sonya D. Zabludoff, Diane M. Simeone, Jonathan Maybaum, Theodore S. Lawrence, and Meredith A. Morgan
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Checkpoint kinase 1 (Chk1) inhibition sensitizes pancreatic cancer cells and tumors to gemcitabine. We hypothesized that Chk1 inhibition would sensitize pancreatic cancer stem cells to gemcitabine. We tested this hypothesis by using two patient-derived xenograft models (designated J and F) and the pancreatic cancer stem cell markers CD24, CD44, and ESA. We determined the percentage of marker-positive cells and their tumor-initiating capacity (by limiting dilution assays) after treatment with gemcitabine and the Chk1 inhibitor, AZD7762. We found that marker-positive cells were significantly reduced by the combination of gemcitabine and AZD7762. In addition, secondary tumor initiation was significantly delayed in response to primary tumor treatment with gemcitabine + AZD7762 compared with control, gemcitabine, or AZD7762 alone. Furthermore, for the same number of stem cells implanted from gemcitabine- versus gemcitabine + AZD7762-treated primary tumors, secondary tumor initiation at 10 weeks was 83% versus 43%, respectively. We also found that pS345 Chk1, which is a measure of DNA damage, was induced in marker-positive cells but not in the marker-negative cells. These data demonstrate that Chk1 inhibition in combination with gemcitabine reduces both the percentage and the tumor-initiating capacity of pancreatic cancer stem cells. Furthermore, the finding that the Chk1-mediated DNA damage response was greater in stem cells than in non-stem cells suggests that Chk1 inhibition may selectively sensitize pancreatic cancer stem cells to gemcitabine, thus making Chk1 a potential therapeutic target for improving pancreatic cancer therapy.
Published: 2012
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28. It sounds Italian, doesn't it? An exploratory analysis on English and Spanish consumer about Italian sounding in the food product market

Author: M. Simeone, Morena Cinquegrana, Carlo Russo, Simeone, M., Cinquegrana, Morena, and Russo, Carlo
Subjects: country of origin, unfair practices, Italian sounding, food culture, food attributes
Abstract: The Italian export of agri-food products has been increasingly threatened by the unfair use of misleading Italian symbols (such as the national flag or the green-white-red colors) by non-Italian producers. This research paper investigated what English and Spanish consumers know about “Made in Italy” food, and their attitude towards Italian appearance food products. Primary data were collected in Spain and England, and a probit model was used to identify the determinants of consumers’ vulnerability to misleading Italian symbols. We found that merely having Italian symbols on the package might lead almost half of the consumers in the sample to consider food as Made in Italy, regardless of the actual origin. This result confirms the severity of the problem. The econometric model provides suggestions for public actions to mitigate the issue.
Published: 2022

29. A Gastric Glycoform of MUC5AC Is a Biomarker of Mucinous Cysts of the Pancreas.

Author: Jessica Sinha, Zheng Cao, Jianliang Dai, Huiyuan Tang, Katie Partyka, Galen Hostetter, Diane M Simeone, Ziding Feng, Peter J Allen, Randall E Brand, and Brian B Haab
Subjects: Medicine, Science
Abstract: Molecular indicators to specify the risk posed by a pancreatic cyst would benefit patients. Previously we showed that most cancer-precursor cysts, termed mucinous cysts, produce abnormal glycoforms of the proteins MUC5AC and endorepellin. Here we sought to validate the glycoforms as a biomarker of mucinous cysts and to specify the oligosaccharide linkages that characterize MUC5AC. We hypothesized that mucinous cysts secrete MUC5AC displaying terminal N-acetylglucosamine (GlcNAc) in either alpha or beta linkage. We used antibody-lectin sandwich assays to detect glycoforms of MUC5AC and endorepellin in cyst fluid samples from three independent cohorts of 49, 32, and 66 patients, and we used monoclonal antibodies to test for terminal, alpha-linked GlcNAc and the enzyme that produces it. A biomarker panel comprising the previously-identified glycoforms of MUC5AC and endorepellin gave 96%, 96%, and 87% accuracy for identifying mucinous cysts in the three cohorts with an average sensitivity of 92% and an average specificity of 94%. Glycan analysis showed that MUC5AC produced by a subset of mucinous cysts displays terminal alpha-GlcNAc, a motif expressed in stomach glands. The alpha-linked glycoform of MUC5AC was unique to intraductal papillary mucinous neoplasms (IPMN), whereas terminal beta-linked GlcNAc was increased in both IPMNs and mucinous cystic neoplasms (MCN). The enzyme that synthesizes alpha-GlcNAc, A4GNT, was expressed in the epithelia of mucinous cysts that expressed alpha-GlcNAc, especially in regions with high-grade dysplasia. Thus IPMNs secrete a gastric glycoform of MUC5AC that displays terminal alpha-GlcNAc, and the combined alpha-GlcNAc and beta-GlcNAc glycoforms form an accurate biomarker of mucinous cysts.
Published: 2016
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30. Post-traumatic stress disorder, anxiety, and depression among adults with congenital heart defects

Author: Regina M. Simeone, Karrie F. Downing, William V. Bobo, Scott D. Grosse, Amber D. Khanna, and Sherry L. Farr
Subjects: Adult, Heart Defects, Congenital, Male, Embryology, Adolescent, Depression, Health, Toxicology and Mutagenesis, Anxiety, Middle Aged, Toxicology, Anxiety Disorders, Article, Stress Disorders, Post-Traumatic, Young Adult, Pediatrics, Perinatology and Child Health, Humans, Female, Developmental Biology
Abstract: BACKGROUND: Due to invasive treatments and stressors related to heart health, adults with congenital heart defects (CHDs) may have an increased risk of post-traumatic stress disorder (PTSD), anxiety, and/or depressive disorders. Our objectives were to estimate the prevalence of these disorders among individuals with CHDs. METHODS: Using IBM(®) MarketScan(®) Databases, we identified adults age 18–49 years with ≥2 outpatient anxiety/depressive disorder claims on separate dates or ≥1 inpatient anxiety/depressive disorder claim in 2017. CHDs were defined as ≥2 outpatient CHD claims ≥30 days apart or ≥1 inpatient CHD claim documented in 2007–2017. We used log-binomial regression to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for associations between CHDs and anxiety/depressive disorders. RESULTS: Of 13,807 adults with CHDs, 12.4% were diagnosed with an anxiety or depressive disorder. Adults with CHDs, compared to the 5,408,094 without CHDs, had higher prevalence of PTSD (0.8% vs. 0.5%; aPR: 1.5 [CI: 1.2–1.8]), anxiety disorders (9.9% vs. 7.5%; aPR: 1.3 [CI: 1.3–1.4]), and depressive disorders (6.3% vs. 4.9%; aPR: 1.3 [CI: 1.2–1.4]). Among individuals with CHDs, female sex (aPR range: 1.6–3.3) and inpatient admission (aPR range 1.1–1.9) were associated with anxiety/depressive disorders. CONCLUSION: Over 1 in 8 adults with CHDs had diagnosed PTSD and/or other anxiety/depressive disorders, 30–50% higher than adults without CHDs. PTSD was rare, but three times more common in women with CHDs than men. Screening and referral for services for these conditions in people with CHDs may be beneficial.
Published: 2021

31. Identification of a specific Vimentin Isoform that induces an antibody response in pancreatic cancer

Author: Su-Hyung Hong, David E. Misek, Hong Wang, Eric Puravs, Robert Hinderer, Thomas J. Giordano, Joel K. Greenson, Dean E. Brenner, Diane M. Simeone, Craig D. Logsdon, and Samir M. Hanash
Subjects: Medicine (General), R5-920
Abstract: Pancreatic cancer has a poor prognosis, in part due to lack of early detection. The identification of circulating tumor antigens or their related autoantibodies provides a means for early cancer diagnosis. We have used a proteomic approach to identify proteins that commonly induce a humoral response in pancreatic cancer. Proteins from a pancreatic adenocarcinoma cell line (Panc-1) were subjected to two-dimensional PAGE, followed by Western blot analysis in which individual sera were tested for autoantibodies. Sera from 36 newly diagnosed patients with pancreatic cancer, 18 patients with chronic pancreatitis and 15 healthy subjects were analyzed. Autoantibodies were detected against a protein identified by mass spectrometry as vimentin, in sera from 16/36 patients with pancreatic cancer (44.4%). Only one of 18 chronic pancreatitis patients and none of the healthy controls exhibited reactivity against this vimentin isoform. Interestingly, none of several other isoforms of vimentin detectable in 2-D gels exhibited reactivity with patient sera. Vimentin protein expression levels were investigated by comparing the integrated intensity of spots visualized in 2-D PAGE gels of various cancers.Pancreatic tumor tissues showed greater than a 3-fold higher expression of total vimentin protein than did the lung, colon, and ovarian tumors that were analyzed. The specifi c antigenic isoform was found at 5-10 fold higher levels. The detection of autoantibodies to this specific isoform of vimentin may have utility for the early diagnosis of pancreatic cancer.
Published: 2006

32. New Labyrinth Microfluidic Device Detects Circulating Tumor Cells Expressing Cancer Stem Cell Marker and Circulating Tumor Microemboli in Hepatocellular Carcinoma

Author: Kaylee J. Smith, Sunitha Nagrath, Eric Lin, Christopher Leu, Diane M. Simeone, G-Su Park, Neehar D. Parikh, Theodore H. Welling, Shanshan Wan, Tae Hyun Kim, John Steffes, Ning Kuo, Thomas Plegue, Nataliya Razimulava, Ryan Delaney, and Hui Guo
Subjects: 0301 basic medicine, Hepatocellular carcinoma, Embolism, Microfluidics, lcsh:Medicine, Metastasis, Translational Research, Biomedical, 0302 clinical medicine, Circulating tumor cell, Lab-On-A-Chip Devices, Neoplasm Metastasis, lcsh:Science, Aged, 80 and over, education.field_of_study, Multidisciplinary, biology, Liver Neoplasms, Hep G2 Cells, Middle Aged, Neoplastic Cells, Circulating, Treatment Outcome, 030220 oncology & carcinogenesis, Disease Progression, Neoplastic Stem Cells, Carcinoma, Hepatocellular, Population, Article, 03 medical and health sciences, Cancer stem cell, Biomarkers, Tumor, Carcinoma, medicine, Humans, education, neoplasms, Aged, business.industry, CD44, lcsh:R, Translational research, medicine.disease, digestive system diseases, 030104 developmental biology, Microscopy, Fluorescence, Drug Resistance, Neoplasm, Tumor progression, biology.protein, Cancer research, lcsh:Q, Neoplasm Recurrence, Local, business
Abstract: Hepatocellular Carcinoma (HCC) is one of the most lethal cancers with a high mortality and recurrence rate. Circulating tumor cell (CTC) detection offers various opportunities to advance early detection and monitoring of HCC tumors which is crucial for improving patient outcome. We developed and optimized a novel Labyrinth microfluidic device to efficiently isolate CTCs from peripheral blood of HCC patients. CTCs were identified in 88.1% of the HCC patients over different tumor stages. The CTC positivity rate was significantly higher in patients with more advanced HCC stages. In addition, 71.4% of the HCC patients demonstrated CTCs positive for cancer stem cell marker, CD44, suggesting that the major population of CTCs could possess stemness properties to facilitate tumor cell survival and dissemination. Furthermore, 55% of the patients had the presence of circulating tumor microemboli (CTM) which also correlated with advanced HCC stage, indicating the association of CTM with tumor progression. Our results show effective CTC capture from HCC patients, presenting a new method for future noninvasive screening and surveillance strategies. Importantly, the detection of CTCs with stemness markers and CTM provides unique insights into the biology of CTCs and their mechanisms influencing metastasis, recurrence and therapeutic resistance.
Published: 2019
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33. Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

Author: Hans A. Kestler, Alexander Kleger, Martin Wagner, Diane M. Simeone, Elodie Roger, Karolin Walter, Bruno Sainz, Johann Gout, Pierre Olivier Frappart, Martin Müller, Michaela Ihle, Thomas Seufferlein, André Lechel, Eva Rodriguez-Aznar, Katja Stifter, Johann M. Kraus, Sebastian Müller, Stefan Liebau, Stephanie Biber, Ninel Azoitei, Roland Rad, Mareen Morawe, Lisa Wiesmüller, Sebastian Lange, Andrea Zamperone, Patrick C. Hermann, Stephan A. Hahn, Elisabeth Hessmann, Lukas Perkhofer, Thomas Engleitner, Frank Arnold, Geography, Laboratory for Medical and Molecular Oncology, Basic (bio-) Medical Sciences, German Cancer Aid, German Research Foundation, Ulm University, Ministry for Science and Culture of Lower Saxony, and Deutsche Krebshilfe
Subjects: 0301 basic medicine, pancreatic tumours, Epithelial-Mesenchymal Transition, DNA Copy Number Variations, DNA Repair, Genotype, Cell Survival, DNA repair, DNA damage, Poly ADP ribose polymerase, medicine.medical_treatment, pancreatic cancer, Drug Resistance, gastroenterology, Apoptosis, Ataxia Telangiectasia Mutated Proteins, Synthetic lethality, Adenocarcinoma, Poly(ADP-ribose) Polymerase Inhibitors, Biology, Targeted therapy, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Homologous Recombination, Pancreas, Drug Synergism, Prognosis, Drug Resistance, Multiple, 3. Good health, Pancreatic Neoplasms, Multiple drug resistance, 030104 developmental biology, 030220 oncology & carcinogenesis, PARP inhibitor, Cancer research, Homologous recombination, Carcinoma, Pancreatic Ductal
Abstract: © Author(s) (or their employer(s)) 2020., [Objective]: ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC)., [Design]: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy., [Results]: Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance., [Conclusion]: Analysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition., Main funding is provided by the German Cancer Aid grant to AK (111879). Additional funding came from the Deutsche Forschungsgemeinschaft (DFG) ’Sachbeihilfe’ (KL 2544/1–1, 1–2, 5–1, 7-1) and ’Heisenberg-Programm’ (KL 2544/6–1), the Baden-Württemberg-Foundation ExPoChip and the INDIMEDVerbund PancChip. AK, FA, MI, SB, LW and TS are either Principal Investigators or students of HEIST RTG funded by the DFG GRK 2254/1. AK is an Else-KrönerFresenius Excellence fellow. LP received funds by the Bausteinprogramm of Ulm University. PCH is supported by a Max Eder Fellowship of the German Cancer Aid (111746), a German Cancer Aid Priority Program ’Translational Oncology’ 70112505 and by a Collaborative Research Centre grant (316249678 – SFB 1279) of the German Research Foundation. EH received funding from the German Cancer Aid (PiPAC, 70112505) and the Volkswagenstiftung/Ministry for Science and Culture in Lower Saxony (ZN3222). This work was also supported by the Deutsche Forschungsgemeinschaft (AZ.96/1–3) to NA, by the Deutsche Krebshilfe (111264) to AL and by the German Cancer Aid Priority Program Translational Oncology (70112504) to LW.
Published: 2021

34. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer.

Author: Ethan V Abel, Edward J Kim, Jingjiang Wu, Mark Hynes, Filip Bednar, Erica Proctor, Lidong Wang, Michele L Dziubinski, and Diane M Simeone
Subjects: Medicine, Science
Abstract: Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized.Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth.Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population.The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.
Published: 2014
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35. Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Author: Tamas A. Gonda, Jessica N. Everett, Michael Wallace, Diane M. Simeone, Laufey Amundadottir, Georg Beyer, Yan Bi, Teresa Brentnall, Darren Carpizo, Alfredo Carrato, Hersh Chandarana, Jennifer Chun, Daniel Chung, Beth Dudley, Julia Earl, Melissa Fava, Srinivas Gaddam, Steve Gallinger, Talia Golan, John Graff, William Greenhalf, Aaron Grossberg, Philip Hart, Spring Holter, Chenchan Huang, Gregory Idos, Priyanka Kanth, Fay Kastrinos, Bryson Katona, Vivek Kaul, Lauren Khanna, Kelsey Klute, Sonia Kupfer, Joy Liau, James Lin, James Lindberg, Andrew Lowy, Aimee Lucas, Julia Mayerle, Nipun Merchant, Salvatore Paiella, Jennifer Permuth, Intan Schrader, Rosalie Sears, Jens Siveke, null Daniel Sussman, and George Zogopoulos
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Heredity, Clinical Decision-Making, Early detection, Endosonography, Predictive Value of Tests, Risk Factors, Pancreatic cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Medical History Taking, Early Detection of Cancer, Aged, Hepatology, business.industry, Incidence, Gastroenterology, Middle Aged, medicine.disease, Prognosis, Pedigree, Pancreatic Neoplasms, Female, business
Published: 2021

36. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author: Stephan B. Dreyer, Rosie Upstill-Goddard, Viola Paulus-Hock, Clara Paris, Eirini-Maria Lampraki, Eloise Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla-Maja Bailey, Marc Jones, Kim Moran-Jones, Derek W. Wright, Fraser Duthie, Karin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances Balkwill, Simon T. Barry, Robert Grützmann, Lola Rahib, Amber Johns, Marina Pajic, Fieke E.M. Froeling, Phillip Beer, Elizabeth A. Musgrove, Gloria M. Petersen, Alan Ashworth, Margaret C. Frame, Howard C. Crawford, Diane M. Simeone, Chris Lord, Debabrata Mukhopadhyay, Christian Pilarsky, David A. Tuveson, Susanna L. Cooke, Nigel B. Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew V. Biankin, David K. Chang, Sarah Allison, Dario Beraldi, Euan Cameron, Stephan Dreyer, Paul Grimwood, Shane Kelly, John Marshall, Sancha Martin, Brian McDade, Daniel McElroy, Donna Ramsay, Derek Wright, Marc D. Jones, Jane Hair, Paul Westwood, Nicola Williams, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, Victorian Cancer Biobank, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Janet S. Graham, and Basic (bio-) Medical Sciences
Subjects: 0301 basic medicine, HRD, homologous recombination deficiency, DNA Repair, PDAC, pancreatic ductal adenocarcinoma, Cell Culture Techniques, DMSO, dimethyl sulfoxide, Transcriptome, 0302 clinical medicine, Molecular Targeted Therapy, SV, structural variation, Original Research, Cancer, PDCL, patient-derived cell line, Gastroenterology, Organoids, PC, pancreatic cancer, oncology, PARP inhibitor, RNAseq, RNA sequencing, 030211 gastroenterology & hepatology, DNA Damage Response, ICGC, International Cancer Genome Consortium, DNA Replication, DNA repair, DNA damage, RPPA, reverse-phase protein array, EC50, median effective concentration, MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, Adenocarcinoma, Biology, DDR, DNA damage response, TOM, topological overlap measure, 03 medical and health sciences, Pancreatic Cancer, Cell Line, Tumor, Pancreatic cancer, GO, Gene Ontology, medicine, Humans, PDX, patient-derived xenograft, Hepatology, DNA replication, Personalized Medicine, Replication Stress, medicine.disease, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, body regions, 030104 developmental biology, siRNA, small interfering RNA, Cancer research, Full Report: Basic and Translational—Pancreas, HR, homologous recombination, Homologous recombination, Biomarkers, DNA Damage
Abstract: Background & Aims Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. Conclusions Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy., Graphical abstract
Published: 2021
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37. Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma.

Author: Erica Proctor, Meghna Waghray, Cheong Jun Lee, David G Heidt, Malica Yalamanchili, Chenwei Li, Filip Bednar, and Diane M Simeone
Subjects: Medicine, Science
Abstract: Bmi1 is an integral component of the Polycomb Repressive Complex 1 (PRC1) and is involved in the pathogenesis of multiple cancers. It also plays a key role in the functioning of endogenous stem cells and cancer stem cells. Previous work implicated a role for cancer stem cells in the pathogenesis of pancreatic cancer. We hypothesized that Bmi1 plays an integral role in enhancing pancreatic tumorigenicity and the function of cancer stem cells in pancreatic ductal adenocarcinoma.We measured endogenous Bmi1 levels in primary human pancreatic ductal adenocarcinomas, pancreatic intraepithelial neoplasias (PanINs) and normal pancreas by immunohistochemistry and Western blotting. The function of Bmi1 in pancreatic cancer was assessed by alteration of Bmi1 expression in several cell model systems by measuring cell proliferation, cell apoptosis, in vitro invasion, chemotherapy resistance, and in vivo growth and metastasis in an orthotopic model of pancreatic cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human pancreatic cancer xenografts after Bmi1 silencing.Bmi1 was overexpressed in human PanINs, pancreatic cancers, and in several pancreatic cancer cell lines. Overexpression of Bmi1 in MiaPaCa2 cells resulted in increased proliferation, in vitro invasion, larger in vivo tumors, more metastases, and gemcitabine resistance while opposite results were seen when Bmi1 was silenced in Panc-1 cells. Bmi1 was overexpressed in the cancer stem cell compartment of primary human pancreatic cancer xenografts. Pancreatic tumorspheres also demonstrated high levels of Bmi1. Silencing of Bmi1 inhibited secondary and tertiary tumorsphere formation, decreased primary pancreatic xenograft growth, and lowered the proportion of cancer stem cells in the xenograft tissue.Our results implicate Bmi1 in the invasiveness and growth of pancreatic cancer and demonstrate its key role in the regulation of pancreatic cancer stem cells.
Published: 2013
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38. Vitamin D receptor activation and photodynamic priming enables durable low-dose chemotherapy

Author: Michael Pigula, Yan Baglo, Diane M. Simeone, Tayyaba Hasan, Sriram Anbil, Pushpamali De Silva, Huang-Chiao Huang, Mari Mino-Kenudson, Imran Rizvi, Mans Broekgaarden, Srivalleesha Mallidi, and Edward V. Maytin
Subjects: 0301 basic medicine, Male, Cancer Research, Receptors, CXCR4, medicine.medical_treatment, Mice, Nude, Antineoplastic Agents, Apoptosis, Calcitriol receptor, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Calcitriol, Low-dose chemotherapy, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, Cell Proliferation, Receptors, CXCR, Tumor microenvironment, Chemotherapy, Performance status, business.industry, Xenograft Model Antitumor Assays, Chemokine CXCL12, Irinotecan, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, 030104 developmental biology, Oncology, Vitamin D3 Receptor, Tolerability, Photochemotherapy, 030220 oncology & carcinogenesis, Cancer research, Receptors, Calcitriol, Dermatologic Agents, business, medicine.drug, Carcinoma, Pancreatic Ductal
Abstract: Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.
Published: 2020

39. Screening for Depression, Sleep-Related Disturbances, and Anxiety in Patients with Adenocarcinoma of the Pancreas: A Preliminary Study

Author: Andrew D. Boyd, Doris Brown, Chris Henrickson, Janet Hampton, Bin Zhu, Farideh Almani, Edgar Ben-Josef, Mark Zalupski, Diane M. Simeone, Jeremy M. G. Taylor, Roseanne Armitage, and Michelle Riba
Subjects: Technology, Medicine, Science
Abstract: Purpose. Screening for depression, sleep-related disturbances, and anxiety in patients with diagnosed adenocarcinoma of the pancreas. Materials and Methods. Patients were evaluated at initial consultation and subsequent visits at the multidisciplinary pancreatic cancer clinic at our University Cancer Center. Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the University of Michigan Sleep Questionnaire to monitor sleep symptoms. Results. Twenty-two patients diagnosed with pancreatic cancer participated during the 6-month pilot study with longitudinal followup for thirteen patients. In this study, mild-to-moderate depressive symptoms, anxiety, and potential sleep problems were common. The main finding of the study was 23% of the patients who were part of this pilot project screened positive for moderately severe major depressive symptoms, likely anxiety disorder or a potential sleep disorder during the study. One patient screened positive for moderately severe depressive symptoms in longitudinal followup. Conclusions. Depression, anxiety, and sleep problems are evident in patients with pancreatic cancer. Prospective, longitudinal studies, with larger groups of patients, are needed to determine if these comorbid symptoms impact outcome and clinical course.
Published: 2012
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40. Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers.

Author: Tingting Yue, Kevin A Maupin, Brian Fallon, Lin Li, Katie Partyka, Michelle A Anderson, Dean E Brenner, Karen Kaul, Herbert Zeh, A James Moser, Diane M Simeone, Ziding Feng, Randall E Brand, and Brian B Haab
Subjects: Medicine, Science
Abstract: The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 531 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (82% sensitivity at 75% specificity for early-stage cancer), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC5AC or MUC16 in all sample sets. By combining measurements of the standard CA 19-9 assay with detection of CA 19-9 on MUC5AC and MUC16, the sensitivity of cancer detection was improved relative to CA 19-9 alone in each sample set, achieving 67-80% sensitivity at 98% specificity. This finding demonstrates the value of measuring glycans on specific proteins for improving biomarker performance. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease.
Published: 2011
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41. CQI PER IL SISTEMA DI IDENTIFICAZIONE ED ANTIBIOGRAMMA IN USO NELL’ A.O. MONALDI - NAPOLI

Author: S. Cuccurullo, M. Di Cecio, V. Naddeo, M. Simeone, M. Falca, and R. Smeraglia
Subjects: Microbiology, QR1-502
Published: 2007
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42. Design and construction of a new detector to measure ultra-low radioactive-isotope contamination of argon

Author: C.E. Aalseth, S. Abdelhakim, F. Acerbi, P. Agnes, R. Ajaj, I.F.M. Albuquerque, T. Alexander, A. Alici, A.K. Alton, P. Amaudruz, F. Ameli, J. Anstey, P. Antonioli, M. Arba, S. Arcelli, R. Ardito, I.J. Arnquist, P. Arpaia, D.M. Asner, A. Asunskis, M. Ave, H.O. Back, V. Barbaryan, A. Barrado Olmedo, G. Batignani, M.G. Bisogni, V. Bocci, A. Bondar, G. Bonfini, W. Bonivento, E. Borisova, B. Bottino, M.G. Boulay, R. Bunker, S. Bussino, A. Buzulutskov, M. Cadeddu, M. Cadoni, A. Caminata, N. Canci, A. Candela, C. Cantini, M. Caravati, M. Cariello, F. Carnesecchi, M. Carpinelli, A. Castellani, P. Castello, S. Catalanotti, V. Cataudella, P. Cavalcante, D. Cavazza, S. Cavuoti, S. Cebrian, J.M. Cela Ruiz, B. Celano, R. Cereseto, W. Cheng, A. Chepurnov, C. Cicalò, L. Cifarelli, M. Citterio, F. Coccetti, A.G. Cocco, V. Cocco, M. Colocci, L. Consiglio, F. Cossio, G. Covone, P. Crivelli, I. D'Antone, M. D'Incecco, D. D'Urso, M.D. Da Rocha Rolo, O. Dadoun, M. Daniel, S. Davini, A. De Candia, S. De Cecco, M. De Deo, A. De Falco, G. De Filippis, D. De Gruttola, G. De Guido, G. De Rosa, G. Dellacasa, P. Demontis, S. DePaquale, A.V. Derbin, A. Devoto, F. Di Eusanio, L. Di Noto, G. Di Pietro, P. Di Stefano, C. Dionisi, G. Dolganov, F. Dordei, M. Downing, F. Edalatfar, A. Empl, M. Fernandez Diaz, A. Ferri, C. Filip, G. Fiorillo, K. Fomenko, A. Franceschi, D. Franco, G.E. Froudakis, F. Gabriele, A. Gabrieli, C. Galbiati, M. Garbini, P. Garcia Abia, D. Gascón Fora, A. Gendotti, C. Ghiano, A. Ghisi, S. Giagu, P. Giampa, R.A. Giampaolo, C. Giganti, M.A. Giorgi, G.K. Giovanetti, M.L. Gligan, A. Gola, O. Gorchakov, M. Grab, R. Graciani Diaz, F. Granato, M. Grassi, J.W. Grate, G.Y. Grigoriev, A. Grobov, M. Gromov, M. Guan, M.B.B. Guerra, M. Guerzoni, M. Gulino, R.K. Haaland, B.R. Hackett, A. Hallin, B. Harrop, E.W. Hoppe, S. Horikawa, B. Hosseini, F. Hubaut, P. Humble, E.V. Hungerford, An. Ianni, A. Ilyasov, V. Ippolito, C. Jillings, K. Keeter, C.L. Kendziora, S. Kim, I. Kochanek, K. Kondo, G. Kopp, D. Korablev, G. Korga, A. Kubankin, R. Kugathasan, M. Kuss, M. Kuźniak, M. La Commara, L. La Delfa, M. Lai, S. Langrock, M. Lebois, B. Lehnert, N. Levashko, X. Li, Q. Liqiang, M. Lissia, G.U. Lodi, G. Longo, R. López Manzano, R. Lussana, L. Luzzi, A.A. Machado, I.N. Machulin, A. Mandarano, L. Mapelli, M. Marcante, A. Margotti, S.M. Mari, M. Mariani, J. Maricic, M. Marinelli, D. Marras, M. Martínez, J.J. Martínez Morales, A.D. Martinez Rojas, C.J. Martoff, M. Mascia, J. Mason, A. Masoni, A. Mazzi, A.B. McDonald, A. Messina, P.D. Meyers, T. Miletic, R. Milincic, A. Moggi, S. Moioli, J. Monroe, M. Morrocchi, T. Mroz, W. Mu, V.N. Muratova, S. Murphy, C. Muscas, P. Musico, R. Nania, T. Napolitano, A. Navrer Agasson, M. Nessi, I. Nikulin, A. Oleinik, V. Oleynikov, M. Orsini, F. Ortica, L. Pagani, M. Pallavicini, S. Palmas, L. Pandola, E. Pantic, E. Paoloni, G. Paternoster, F. Pazzona, S. Peeters, P.A. Pegoraro, K. Pelczar, L.A. Pellegrini, C. Pellegrino, N. Pelliccia, F. Perotti, V. Pesudo, E. Picciau, C. Piemonte, F. Pietropaolo, A. Pocar, T.R. Pollmann, D. Portaluppi, S.S. Poudel, P. Pralavorio, D. Price, B. Radics, F. Raffaelli, F. Ragusa, M. Razeti, A. Razeto, V. Regazzoni, C. Regenfus, A.L. Renshaw, S. Rescia, M. Rescigno, F. Retiere, L.P. Rignanese, A. Rivetti, A. Romani, L. Romero, N. Rossi, A. Rubbia, D. Sablone, P. Sala, P. Salatino, O. Samoylov, E. Sánchez García, S. Sanfilippo, M. Sant, D. Santone, R. Santorelli, C. Savarese, E. Scapparone, B. Schlitzer, G. Scioli, E. Segreto, A. Seifert, D.A. Semenov, A. Shchagin, A. Sheshukov, S. Siddhanta, M. Simeone, P.N. Singh, P. Skensved, M.D. Skorokhvatov, O. Smirnov, G. Sobrero, A. Sokolov, A. Sotnikov, R. Stainforth, A. Steri, S. Stracka, V. Strickland, G.B. Suffritti, S. Sulis, Y. Suvorov, A.M. Szelc, R. Tartaglia, G. Testera, T. Thorpe, A. Tonazzo, A. Tosi, M. Tuveri, E.V. Unzhakov, G. Usai, A. Vacca, E. Vázquez-Jáuregui, M. Verducci, T. Viant, S. Viel, F. Villa, A. Vishneva, R.B. Vogelaar, M. Wada, J. Wahl, J.J. Walding, H. Wang, Y. Wang, S. Westerdale, R.J. Wheadon, R. Williams, J. Wilson, Marcin Wojcik, Mariusz Wojcik, S. Wu, X. Xiao, C. Yang, Z. Ye, M. Zuffa, G. Zuzel, Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Fondazione Bruno Kessler [Trento, Italy] (FBK), Trento Institute for Fundamental Physics and Applications, Italy, AstroParticule et Cosmologie (APC (UMR_7164)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Fédératif de Recherche en Sciences et Ingénierie de la Santé (IFRESIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-IFR143, University of Surrey (UNIS), Aalseth, C, Abdelhakim, S, Acerbi, F, Agnes, P, Ajaj, R, Albuquerque, I, Alexander, T, Alici, A, Alton, A, Amaudruz, P, Ameli, F, Anstey, J, Antonioli, P, Arba, M, Arcelli, S, Ardito, R, Arnquist, I, Arpaia, P, Asner, D, Asunskis, A, Ave, M, Back, H, Barbaryan, V, Barrado Olmedo, A, Batignani, G, Bisogni, M, Bocci, V, Bondar, A, Bonfini, G, Bonivento, W, Borisova, E, Bottino, B, Boulay, M, Bunker, R, Bussino, S, Buzulutskov, A, Cadeddu, M, Cadoni, M, Caminata, A, Canci, N, Candela, A, Cantini, C, Caravati, M, Cariello, M, Carnesecchi, F, Carpinelli, M, Castellani, A, Castello, P, Catalanotti, S, Cataudella, V, Cavalcante, P, Cavazza, D, Cavuoti, S, Cebrian, S, Cela Ruiz, J, Celano, B, Cereseto, R, Cheng, W, Chepurnov, A, Cicalo, C, Cifarelli, L, Citterio, M, Coccetti, F, Cocco, A, Cocco, V, Colocci, M, Consiglio, L, Cossio, F, Covone, G, Crivelli, P, D'Antone, I, D'Incecco, M, D'Urso, D, da Rocha Rolo, M, Dadoun, O, Daniel, M, Davini, S, de Candia, A, de Cecco, S, de Deo, M, de Falco, A, de Filippis, G, de Gruttola, D, de Guido, G, de Rosa, G, Dellacasa, G, Demontis, P, Depaquale, S, Derbin, A, Devoto, A, Di Eusanio, F, Di Noto, L, Di Pietro, G, Di Stefano, P, Dionisi, C, Dolganov, G, Dordei, F, Downing, M, Edalatfar, F, Empl, A, Fernandez Diaz, M, Ferri, A, Filip, C, Fiorillo, G, Fomenko, K, Franceschi, A, Franco, D, Froudakis, G, Gabriele, F, Gabrieli, A, Galbiati, C, Garbini, M, Garcia Abia, P, Gascon Fora, D, Gendotti, A, Ghiano, C, Ghisi, A, Giagu, S, Giampa, P, Giampaolo, R, Giganti, C, Giorgi, M, Giovanetti, G, Gligan, M, Gola, A, Gorchakov, O, Grab, M, Graciani Diaz, R, Granato, F, Grassi, M, Grate, J, Grigoriev, G, Grobov, A, Gromov, M, Guan, M, Guerra, M, Guerzoni, M, Gulino, M, Haaland, R, Hackett, B, Hallin, A, Harrop, B, Hoppe, E, Horikawa, S, Hosseini, B, Hubaut, F, Humble, P, Hungerford, E, Ianni, A, Ilyasov, A, Ippolito, V, Jillings, C, Keeter, K, Kendziora, C, Kim, S, Kochanek, I, Kondo, K, Kopp, G, Korablev, D, Korga, G, Kubankin, A, Kugathasan, R, Kuss, M, Kuzniak, M, la Commara, M, la Delfa, L, Lai, M, Langrock, S, Lebois, M, Lehnert, B, Levashko, N, Li, X, Liqiang, Q, Lissia, M, Lodi, G, Longo, G, Lopez Manzano, R, Lussana, R, Luzzi, L, Machado, A, Machulin, I, Mandarano, A, Mapelli, L, Marcante, M, Margotti, A, Mari, S, Mariani, M, Maricic, J, Marinelli, M, Marras, D, Martinez, M, Martinez Morales, J, Martinez Rojas, A, Martoff, C, Mascia, M, Mason, J, Masoni, A, Mazzi, A, Mcdonald, A, Messina, A, Meyers, P, Miletic, T, Milincic, R, Moggi, A, Moioli, S, Monroe, J, Morrocchi, M, Mroz, T, Mu, W, Muratova, V, Murphy, S, Muscas, C, Musico, P, Nania, R, Napolitano, T, Navrer Agasson, A, Nessi, M, Nikulin, I, Oleinik, A, Oleynikov, V, Orsini, M, Ortica, F, Pagani, L, Pallavicini, M, Palmas, S, Pandola, L, Pantic, E, Paoloni, E, Paternoster, G, Pazzona, F, Peeters, S, Pegoraro, P, Pelczar, K, Pellegrini, L, Pellegrino, C, Pelliccia, N, Perotti, F, Pesudo, V, Picciau, E, Piemonte, C, Pietropaolo, F, Pocar, A, Pollmann, T, Portaluppi, D, Poudel, S, Pralavorio, P, Price, D, Radics, B, Raffaelli, F, Ragusa, F, Razeti, M, Razeto, A, Regazzoni, V, Regenfus, C, Renshaw, A, Rescia, S, Rescigno, M, Retiere, F, Rignanese, L, Rivetti, A, Romani, A, Romero, L, Rossi, N, Rubbia, A, Sablone, D, Sala, P, Salatino, P, Samoylov, O, Sanchez Garcia, E, Sanfilippo, S, Sant, M, Santone, D, Santorelli, R, Savarese, C, Scapparone, E, Schlitzer, B, Scioli, G, Segreto, E, Seifert, A, Semenov, D, Shchagin, A, Sheshukov, A, Siddhanta, S, Simeone, M, Singh, P, Skensved, P, Skorokhvatov, M, Smirnov, O, Sobrero, G, Sokolov, A, Sotnikov, A, Stainforth, R, Steri, A, Stracka, S, Strickland, V, Suffritti, G, Sulis, S, Suvorov, Y, Szelc, A, Tartaglia, R, Testera, G, Thorpe, T, Tonazzo, A, Tosi, A, Tuveri, M, Unzhakov, E, Usai, G, Vacca, A, Vazquez-Jauregui, E, Verducci, M, Viant, T, Viel, S, Villa, F, Vishneva, A, Vogelaar, R, Wada, M, Wahl, J, Walding, J, Wang, H, Wang, Y, Westerdale, S, Wheadon, R, Williams, R, Wilson, J, Wojcik, M, Wu, S, Xiao, X, Yang, C, Ye, Z, Zuffa, M, Zuzel, G, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Fédératif de Recherche en Sciences et Ingénierie de la Santé (IFRESIS), Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure des Mines de St Etienne (ENSM ST-ETIENNE)-Centre National de la Recherche Scientifique (CNRS), Aalseth, C. E., Abdelhakim, S., Acerbi, F., Agnes, P., Ajaj, R., Albuquerque, I. F. M., Alexander, T., Alici, A., Alton, A. K., Amaudruz, P., Ameli, F., Anstey, J., Antonioli, P., Arba, M., Arcelli, S., Ardito, R., Arnquist, I. J., Arpaia, P., Asner, D. M., Asunskis, A., Ave, M., Back, H. O., Barbaryan, V., Olmedo, A. Barrado, Batignani, G., Bisogni, M. G., Bocci, V., Bondar, A., Bonfini, G., Bonivento, W., Borisova, E., Bottino, B., Boulay, M. G., Bunker, R., Bussino, S., Buzulutskov, A., Cadeddu, M., Cadoni, M., Caminata, A., Canci, N., Candela, A., Cantini, C., Caravati, M., Cariello, M., Carnesecchi, F., Carpinelli, M., Castellani, A., Castello, P., Catalanotti, S., Cataudella, V., Cavalcante, P., Cavazza, D., Cavuoti, S., Cebrian, S., Ruiz, J. M. Cela, Celano, B., Cereseto, R., Cheng, W., Chepurnov, A., Cicalò, C., Cifarelli, L., Citterio, M., Coccetti, F., Cocco, A. G., Cocco, V., Colocci, M., Consiglio, L., Cossio, F., Covone, G., Crivelli, P., D'Antone, I., D'Incecco, M., D'Urso, D., Rolo, M. D. Da Rocha, Dadoun, O., Daniel, M., Davini, S., Candia, A. De, Cecco, S. De, Deo, M. De, Falco, A. De, Filippis, G. De, Gruttola, D. De, Guido, G. De, Rosa, G. De, Dellacasa, G., Demontis, P., Depaquale, S., Derbin, A. V., Devoto, A., Eusanio, F. Di, Noto, L. Di, Pietro, G. Di, Stefano, P. Di, Dionisi, C., Dolganov, G., Dordei, F., Downing, M., Edalatfar, F., Empl, A., Diaz, M. Fernandez, Ferri, A., Filip, C., Fiorillo, G., Fomenko, K., Franceschi, A., Franco, D., Froudakis, G. E., Gabriele, F., Gabrieli, A., Galbiati, C., Garbini, M., Abia, P. Garcia, Fora, D. Gascón, Gendotti, A., Ghiano, C., Ghisi, A., Giagu, S., Giampa, P., Giampaolo, R. A., Giganti, C., Giorgi, M. A., Giovanetti, G. K., Gligan, M. L., Gola, A., Gorchakov, O., Grab, M., Diaz, R. Graciani, Granato, F., Grassi, M., Grate, J. W., Grigoriev, G. Y., Grobov, A., Gromov, M., Guan, M., Guerra, M. B. B., Guerzoni, M., Gulino, M., Haaland, R. K., Hackett, B. R., Hallin, A., Harrop, B., Hoppe, E. W., Horikawa, S., Hosseini, B., Hubaut, F., Humble, P., Hungerford, E. V., Ianni, An., Ilyasov, A., Ippolito, V., Jillings, C., Keeter, K., Kendziora, C. L., Kim, S., Kochanek, I., Kondo, K., Kopp, G., Korablev, D., Korga, G., Kubankin, A., Kugathasan, R., Kuss, M., Kuźniak, M., Commara, M. La, Delfa, L. La, Lai, M., Langrock, S., Lebois, M., Lehnert, B., Levashko, N., Li, X., Liqiang, Q., Lissia, M., Lodi, G. U., Longo, G., Manzano, R. López, Lussana, R., Luzzi, L., Machado, A. A., Machulin, I. N., Mandarano, A., Mapelli, L., Marcante, M., Margotti, A., Mari, S. M., Mariani, M., Maricic, J., Marinelli, M., Marras, D., Martínez, M., Morales, J. J. Martínez, Rojas, A. D. Martinez, Martoff, C. J., Mascia, M., Mason, J., Masoni, A., Mazzi, A., Mcdonald, A. B., Messina, A., Meyers, P. D., Miletic, T., Milincic, R., Moggi, A., Moioli, S., Monroe, J., Morrocchi, M., Mroz, T., Mu, W., Muratova, V. N., Murphy, S., Muscas, C., Musico, P., Nania, R., Napolitano, T., Agasson, A. Navrer, Nessi, M., Nikulin, I., Oleinik, A., Oleynikov, V., Orsini, M., Ortica, F., Pagani, L., Pallavicini, M., Palmas, S., Pandola, L., Pantic, E., Paoloni, E., Paternoster, G., Pazzona, F., Peeters, S., Pegoraro, P. A., Pelczar, K., Pellegrini, L. A., Pellegrino, C., Pelliccia, N., Perotti, F., Pesudo, V., Picciau, E., Piemonte, C., Pietropaolo, F., Pocar, A., Pollmann, T. R., Portaluppi, D., Poudel, S. S., Pralavorio, P., Price, D., Radics, B., Raffaelli, F., Ragusa, F., Razeti, M., Razeto, A., Regazzoni, V., Regenfus, C., Renshaw, A. L., Rescia, S., Rescigno, M., Retiere, F., Rignanese, L. P., Rivetti, A., Romani, A., Romero, L., Rossi, N., Rubbia, A., Sablone, D., Sala, P., Salatino, P., Samoylov, O., García, E. Sánchez, Sanfilippo, S., Sant, M., Santone, D., Santorelli, R., Savarese, C., Scapparone, E., Schlitzer, B., Scioli, G., Segreto, E., Seifert, A., Semenov, D. A., Shchagin, A., Sheshukov, A., Siddhanta, S., Simeone, M., Singh, P. N., Skensved, P., Skorokhvatov, M. D., Smirnov, O., Sobrero, G., Sokolov, A., Sotnikov, A., Stainforth, R., Steri, A., Stracka, S., Strickland, V., Suffritti, G. B., Sulis, S., Suvorov, Y., Szelc, A. M., Tartaglia, R., Testera, G., Thorpe, T., Tonazzo, A., Tosi, A., Tuveri, M., Unzhakov, E. V., Usai, G., Vacca, A., Vázquez-Jáuregui, E., Verducci, M., Viant, T., Viel, S., Villa, F., Vishneva, A., Vogelaar, R. B., Wada, M., Wahl, J., Walding, J. J., Wang, H., Wang, Y., Westerdale, S., Wheadon, R. J., Williams, R., Wilson, J., Wojcik, Marcin, Wojcik, Mariusz, Wu, S., Xiao, X., Yang, C., Ye, Z., Zuffa, M., Zuzel, G., Aalseth C.E., Abdelhakim S., Acerbi F., Agnes P., Ajaj R., Albuquerque I.F.M., Alexander T., Alici A., Alton A.K., Amaudruz P., Ameli F., Anstey J., Antonioli P., Arba M., Arcelli S., Ardito R., Arnquist I.J., Arpaia P., Asner D.M., Asunskis A., Ave M., Back H.O., Barbaryan V., Barrado Olmedo A., Batignani G., Bisogni M.G., Bocci V., Bondar A., Bonfini G., Bonivento W., Borisova E., Bottino B., Boulay M.G., Bunker R., Bussino S., Buzulutskov A., Cadeddu M., Cadoni M., Caminata A., Canci N., Candela A., Cantini C., Caravati M., Cariello M., Carnesecchi F., Carpinelli M., Castellani A., Castello P., Catalanotti S., Cataudella V., Cavalcante P., Cavazza D., Cavuoti S., Cebrian S., Cela Ruiz J.M., Celano B., Cereseto R., Cheng W., Chepurnov A., Cicalo C., Cifarelli L., Citterio M., Coccetti F., Cocco A.G., Cocco V., Colocci M., Consiglio L., Cossio F., Covone G., Crivelli P., D'Antone I., D'Incecco M., D'Urso D., da Rocha Rolo M.D., Dadoun O., Daniel M., Davini S., de Candia A., de Cecco S., de Deo M., de Falco A., de Filippis G., de Gruttola D., de Guido G., de Rosa G., Dellacasa G., Demontis P., DePaquale S., Derbin A.V., Devoto A., Di Eusanio F., Di Noto L., Di Pietro G., Di Stefano P., Dionisi C., Dolganov G., Dordei F., Downing M., Edalatfar F., Empl A., Fernandez Diaz M., Ferri A., Filip C., Fiorillo G., Fomenko K., Franceschi A., Franco D., Froudakis G.E., Gabriele F., Gabrieli A., Galbiati C., Garbini M., Garcia Abia P., Gascon Fora D., Gendotti A., Ghiano C., Ghisi A., Giagu S., Giampa P., Giampaolo R.A., Giganti C., Giorgi M.A., Giovanetti G.K., Gligan M.L., Gola A., Gorchakov O., Grab M., Graciani Diaz R., Granato F., Grassi M., Grate J.W., Grigoriev G.Y., Grobov A., Gromov M., Guan M., Guerra M.B.B., Guerzoni M., Gulino M., Haaland R.K., Hackett B.R., Hallin A., Harrop B., Hoppe E.W., Horikawa S., Hosseini B., Hubaut F., Humble P., Hungerford E.V., Ianni An., Ilyasov A., Ippolito V., Jillings C., Keeter K., Kendziora C.L., Kim S., Kochanek I., Kondo K., Kopp G., Korablev D., Korga G., Kubankin A., Kugathasan R., Kuss M., Kuzniak M., la Commara M., la Delfa L., Lai M., Langrock S., Lebois M., Lehnert B., Levashko N., Li X., Liqiang Q., Lissia M., Lodi G.U., Longo G., Lopez Manzano R., Lussana R., Luzzi L., Machado A.A., Machulin I.N., Mandarano A., Mapelli L., Marcante M., Margotti A., Mari S.M., Mariani M., Maricic J., Marinelli M., Marras D., Martinez M., Martinez Morales J.J., Martinez Rojas A.D., Martoff C.J., Mascia M., Mason J., Masoni A., Mazzi A., McDonald A.B., Messina A., Meyers P.D., Miletic T., Milincic R., Moggi A., Moioli S., Monroe J., Morrocchi M., Mroz T., Mu W., Muratova V.N., Murphy S., Muscas C., Musico P., Nania R., Napolitano T., Navrer Agasson A., Nessi M., Nikulin I., Oleinik A., Oleynikov V., Orsini M., Ortica F., Pagani L., Pallavicini M., Palmas S., Pandola L., Pantic E., Paoloni E., Paternoster G., Pazzona F., Peeters S., Pegoraro P.A., Pelczar K., Pellegrini L.A., Pellegrino C., Pelliccia N., Perotti F., Pesudo V., Picciau E., Piemonte C., Pietropaolo F., Pocar A., Pollmann T.R., Portaluppi D., Poudel S.S., Pralavorio P., Price D., Radics B., Raffaelli F., Ragusa F., Razeti M., Razeto A., Regazzoni V., Regenfus C., Renshaw A.L., Rescia S., Rescigno M., Retiere F., Rignanese L.P., Rivetti A., Romani A., Romero L., Rossi N., Rubbia A., Sablone D., Sala P., Salatino P., Samoylov O., Sanchez Garcia E., Sanfilippo S., Sant M., Santone D., Santorelli R., Savarese C., Scapparone E., Schlitzer B., Scioli G., Segreto E., Seifert A., Semenov D.A., Shchagin A., Sheshukov A., Siddhanta S., Simeone M., Singh P.N., Skensved P., Skorokhvatov M.D., Smirnov O., Sobrero G., Sokolov A., Sotnikov A., Stainforth R., Steri A., Stracka S., Strickland V., Suffritti G.B., Sulis S., Suvorov Y., Szelc A.M., Tartaglia R., Testera G., Thorpe T., Tonazzo A., Tosi A., Tuveri M., Unzhakov E.V., Usai G., Vacca A., Vazquez-Jauregui E., Verducci M., Viant T., Viel S., Villa F., Vishneva A., Vogelaar R.B., Wada M., Wahl J., Walding J.J., Wang H., Wang Y., Westerdale S., Wheadon R.J., Williams R., Wilson J., Wojcik M., Wu S., Xiao X., Yang C., Ye Z., Zuffa M., Zuzel G., Barrado Olmedo, A., Cela Ruiz, J. M., Da Rocha Rolo, M. D., De Candia, A., De Cecco, S., De Deo, M., De Falco, A., De Filippis, G., De Gruttola, D., De Guido, G., De Rosa, G., Di Eusanio, F., Di Noto, L., Di Pietro, G., Di Stefano, P., Fernandez Diaz, M., Garcia Abia, P., Gascón Fora, D., Graciani Diaz, R., La Commara, M., La Delfa, L., López Manzano, R., Martínez Morales, J. J., Martinez Rojas, A. D., Navrer Agasson, A., Sánchez García, E., and Szelcc, A. M.
Subjects: Physics - Instrumentation and Detectors, gas and liquid scintillators), axions, Physics::Instrumentation and Detectors, Noble liquid detectors (scintillation, ionization, double-phase), 01 natural sciences, 030218 nuclear medicine & medical imaging, Dark Matter detectors (WIMPs, axions, etc.), 0302 clinical medicine, Recoil, Noble liquid detectors (scintillation, ionization, double-phase), Dark Matter detectors (WIMPs, axions, etc.), Cryogenic detectors, Scintillators, scintillation and light emission processes (solid, gas and liquid scintillators), Noble liquid detectors (scintillation, Cryogenic detectors, Scintillation and light emission processes (solid, gas, liquid scintillators), Scintillators, etc.), [PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex], Detectors and Experimental Techniques, physics.ins-det, Instrumentation, Mathematical Physics, Physics, Scintillation and light emission processes (solid, Time projection chamber, Detector, Instrumentation and Detectors (physics.ins-det), double-phase), Dark Matter detectors(WIMPs, axions, etc.), Scintillators, scintillation and light emission processes(solid, gas and liquid scintillators), scintillation and light emission processes(solid, Weakly interacting massive particles, Astrophysics - Instrumentation and Methods for Astrophysics, Astrophysics and Astronomy, Dark matter, Cryogenic detector, chemistry.chemical_element, FOS: Physical sciences, Nuclear physics, 03 medical and health sciences, gas, ionization, 0103 physical sciences, liquid scintillators), Instrumentation and Methods for Astrophysics (astro-ph.IM), Dark Matter detectors (WIMPs, Argon, 010308 nuclear & particles physics, Canfranc Underground Laboratory, Scintillator, Dark Matter detectors(WIMPs, chemistry, astro-ph.IM, ArDM
Abstract: Large liquid argon detectors offer one of the best avenues for the detection of galactic weakly interacting massive particles (WIMPs) via their scattering on atomic nuclei. The liquid argon target allows exquisite discrimination between nuclear and electron recoil signals via pulse-shape discrimination of the scintillation signals. Atmospheric argon (AAr), however, has a naturally occurring radioactive isotope, $^{39}$Ar, a $\beta$ emitter of cosmogenic origin. For large detectors, the atmospheric $^{39}$Ar activity poses pile-up concerns. The use of argon extracted from underground wells, deprived of $^{39}$Ar, is key to the physics potential of these experiments. The DarkSide-20k dark matter search experiment will operate a dual-phase time projection chamber with 50 tonnes of radio-pure underground argon (UAr), that was shown to be depleted of $^{39}$Ar with respect to AAr by a factor larger than 1400. Assessing the $^{39}$Ar content of the UAr during extraction is crucial for the success of DarkSide-20k, as well as for future experiments of the Global Argon Dark Matter Collaboration (GADMC). This will be carried out by the DArT in ArDM experiment, a small chamber made with extremely radio-pure materials that will be placed at the centre of the ArDM detector, in the Canfranc Underground Laboratory (LSC) in Spain. The ArDM LAr volume acts as an active veto for background radioactivity, mostly $\gamma$-rays from the ArDM detector materials and the surrounding rock. This article describes the DArT in ArDM project, including the chamber design and construction, and reviews the background required to achieve the expected performance of the detector., Comment: 13 pages, 8 figures. Corresponding author: E. S\'anchez Garc\'ia
Published: 2020
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43. HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Author: Holly Brunton, Giuseppina Caligiuri, Richard Cunningham, Rosie Upstill-Goddard, Ulla-Maja Bailey, Ian M. Garner, Craig Nourse, Stephan Dreyer, Marc Jones, Kim Moran-Jones, Derek W. Wright, Viola Paulus-Hock, Colin Nixon, Gemma Thomson, Nigel B. Jamieson, Grant A. McGregor, Lisa Evers, Colin J. McKay, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephen J. Pettitt, Michele L. Dziubinski, Simon T. Barry, Robert Grützmann, Robert Brown, Edward Curry, Marina Pajic, Elizabeth A. Musgrove, Gloria M. Petersen, Emma Shanks, Alan Ashworth, Howard C. Crawford, Diane M. Simeone, Fieke E.M. Froeling, Christopher J. Lord, Debabrata Mukhopadhyay, Christian Pilarsky, Sean E. Grimmond, Jennifer P. Morton, Owen J. Sansom, David K. Chang, Peter J. Bailey, Andrew V. Biankin, Sarah Allison, Susanna L. Cooke, Paul Grimwood, Shane Kelly, John Marshall, Brian McDade, Daniel McElroy, Donna Ramsay, Selma Rebus, Jane Hair, Paul Westwood, Nicola Williams, Fraser Duthie, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Janet S. Graham, and Basic (bio-) Medical Sciences
Subjects: 0301 basic medicine, Biology, Adenocarcinoma, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, GATA6, GSK-3, Pancreatic cancer, Cell Line, Tumor, GATA6 Transcription Factor, medicine, Biomarkers, Tumor, Humans, GSK3B, chromatin landscapes, metabolic targeting, intronic and distal promoters, medicine.disease, Phenotype, HNF4A, Chromatin, 030104 developmental biology, Hepatocyte nuclear factor 4, Hepatocyte Nuclear Factor 4, PDAC subtypes, oncology, Cancer research, therapeutic tolerance, 030217 neurology & neurosurgery, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.
Published: 2020

44. Specific birth defects in pregnancies of women with diabetes: National Birth Defects Prevention Study, 1997–2011

Author: Jennita Reefhuis, Cynthia A. Moore, Shin Y. Kim, D. Kim Waller, Suzanne M. Gilboa, Denise J. Jamieson, Lorenzo D. Botto, Regina M. Simeone, and Sarah C. Tinker
Subjects: education.field_of_study, medicine.medical_specialty, Pregnancy, Type 1 diabetes, 030219 obstetrics & reproductive medicine, Obstetrics, business.industry, Population, Case-control study, Obstetrics and Gynecology, General Medicine, Odds ratio, Type 2 diabetes, medicine.disease, Article, Gestational diabetes, Prevention Study, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, medicine, 030212 general & internal medicine, education, business
Abstract: BACKGROUND: Diabetes is associated with an increased risk for many birth defects and is likely to have an increasing impact on birth defect prevalence because of the rise in diabetes in the United States in recent decades. One of the first analyses in which specific birth defects were assessed for their relationship with both pregestational and gestational diabetes used data from the initial 6 years of the National Birth Defects Prevention Study. That analysis reported strong associations for pregestational diabetes with several birth defects, but few exposures among some of the less common birth defects led to unstable estimates with wide confidence intervals. Since that analysis, the study continued to collect data for another 8 years, including information on approximately 19,000 additional cases and 6900 additional controls. OBJECTIVE: Our objective was to use data from the National Birth Defects Prevention Study, the largest population-based birth defects case-control study in the United States, to provide updated and more precise estimates of the association between diabetes and birth defects, including some defects not previously assessed. STUDY DESIGN: We analyzed data on deliveries from October 1997 through December 2011. Mothers of case and control infants were interviewed about their health conditions and exposures during pregnancy, including diagnosis of pregestational (type 1 or type 2) diabetes before the index pregnancy or gestational diabetes during the index pregnancy. Using logistic regression, we separately assessed the association between pregestational and gestational diabetes with specific categories of structural birth defects for which there were at least 3 exposed case infants. For birth defect categories for which there were at least 5 exposed case infants, we calculated odds ratios adjusted for maternal body mass index, age, education, race/ethnicity, and study site; for defect categories with 3 or 4 exposed cases, we calculated crude odds ratios. RESULTS: Pregestational diabetes was reported by 0.6% of mothers of control infants (71 of 11,447) and 2.5% of mothers of case infants (775 of 31,007). Gestational diabetes during the index pregnancy was reported by 4.7% of mothers of control infants (536 of 11,447) and 5.3% of mothers of case infants (1,653 of 31,007). Pregestational diabetes was associated with strong, statistically significant odds ratios (range, 2.5–80.2) for 46 of 50 birth defects considered. The largest odds ratio was observed for sacral agenesis (adjusted odds ratio, 80.2; 95% confidence interval, 46.1–139.3). A greater than 10-fold increased risk was also observed for holoprosencephaly (adjusted odds ratio, 13.1; 95% confidence interval, 7.0–24.5), longitudinal limb deficiency (adjusted odds ratio, 10.1; 95% confidence interval, 6.2–16.5), heterotaxy (adjusted odds ratio, 12.3; 95% confidence interval, 7.3–20.5), truncus arteriosus (adjusted odds ratio, 14.9; 95% confidence interval, 7.6–29.3), atrioventricular septal defect (adjusted odds ratio, 10.5; 95% confidence interval, 6.2–17.9), and single ventricle complex (adjusted odds ratio, 14.7; 95% confidence interval, 8.9–24.3). For gestational diabetes, statistically significant odds ratios were fewer (12 of 56) and of smaller magnitude (range, 1.3– 2.1; 0.5 for gastroschisis). CONCLUSION: Pregestational diabetes is associated with a markedly increased risk for many specific births defects. Because glycemic control before pregnancy is associated with a reduced risk for birth defects, ongoing quality care for persons with diabetes is an important opportunity for prevention.
Published: 2019

45. Zika Pregnancy Surveillance: Transforming Data into Educational and Clinical Tools

Author: Jazmyn Moore, Dana Meaney-Delman, Regina M. Simeone, Samantha M. Olson, Sascha Ellinton, Titilope Oduyebo, Kara N. D. Polen, and Margaret A. Honein
Subjects: Pregnancy, medicine.medical_specialty, biology, business.industry, Public health, Patient counseling, medicine.disease, biology.organism_classification, Zika virus, Outreach, General Earth and Planetary Sciences, Medicine, Health education, Professional association, Medical emergency, business, Healthcare providers, Abstract, General Environmental Science
Abstract: Objective To describe how Zika virus (Zika) surveillance data informs and improves testing guidance, clinical evaluation and management of pregnant women and infants with possible Zika infection Introduction Little was known about the maternal and fetal/infant effects of Zika infection before the 2015 outbreak in the Americas, which made it challenging for public health practitioners and clinicians to care for pregnant women and infants exposed to Zika. In 2016, CDC implemented a rapid surveillance system, the US Zika Pregnancy and Infant Registry, to collect information about the impact of Zika infection during pregnancy and inform the CDC response and clinical guidance. In partnership with state, tribal, local, and territorial health departments, CDC disseminated information from this surveillance system, which served as the foundation for educational materials and clinical tools for healthcare providers. Methods Throughout the Zika response, CDC worked closely with health officers, epidemiologists, and clinical partners to seek expert input on the interpretation of emerging data and the evaluation and management of these vulnerable populations. In response to requests from clinical and public health partners, CDC created targeted educational materials and tools to facilitate the implementation of clinical guidance. These materials equipped healthcare providers with the information needed to care for pregnant women and infants with Zika infection. Examples of products developed included: 1) screening tools to identify pregnant women for whom testing is indicated; 2) an interactive web tool to assist with implementation and interpretation of Zika testing guidance (Pregnancy and Zika Testing Widget); 3) patient counseling scripts; and 4) videos to explain critical clinical concepts (e.g., measurement of infant head circumference). These tools were informally pre-tested with the target audiences prior to dissemination, specifically to assess usefulness in clinical settings. CDC disseminated these tools through the CDC website and through comprehensive outreach (e.g., webinars, calls, email alerts) to various audiences. Additionally, several professional organizations incorporated these tools into regular communication with their membership. Results The US Zika Pregnancy and Infant Registry is currently monitoring infants from approximately 7,300 pregnancies in the US states and territories with laboratory evidence of Zika. Surveillance data provided valuable information, including clues toward the pattern of defects and other neurologic disabilities associated with congenital Zika infection, estimates of the risks associated with congenital infection, and timeframes of greatest risk during pregnancy, to help clinicians counsel pregnant patients with potential Zika exposure. CDC used these data to inform their clinical tools, particularly in pretest counseling materials and educational factsheets for healthcare providers to use with pregnant women with potential Zika exposure. After informal testing among healthcare providers, the tools received positive feedback regarding usefulness and applicability in clinical settings. Collectively, CDC’s Zika clinical tools were downloaded more than 300,000 times from CDC’s website. The Pregnancy and Zika Testing Widget was accessed and followed to an endpoint (e.g., Zika testing recommended) more than 17,000 times, with more than 75% of users self-identifying as clinicians. Conclusions Rapid implementation of Zika surveillance captured evolving data about the impact of Zika on pregnant women and their infants. These data informed the development of clinical tools for healthcare providers caring for and counseling patients with Zika exposure. These tools ensured pregnant women and infants were adequately monitored during the Zika outbreak. Health education materials and clinical tools based on surveillance data should be considered in future emergency responses, particularly when knowledge is rapidly evolving. References CDC Zika Pregnancy Website: https://www.cdc.gov/pregnancy/zika/materials/index.html
Published: 2019

46. Groundwater quality in the Mediterranean region

Author: Mongelli, G. Argyraki, A. García Lorenzo, M.L. Shammout, M.W. Paternoster, M. Simeone, V.
Published: 2019

47. Mucin acts as a nutrient source and a signal for the differential expression of genes coding for cellular processes and virulence factors in Acinetobacter baumannii

Author: Luis A. Actis, Steven E. Fiester, Cecily R. Wood, Maeva L. Metz, Gabriella M. Simeone, Emily J. Ohneck, and Brock A. Arivett
Subjects: Acinetobacter baumannii, 0301 basic medicine, Pulmonology, Operon, Secretion Systems, Pathogenesis, Pathology and Laboratory Medicine, Biochemistry, Microbial Physiology, Nucleic Acids, Gene expression, Medicine and Health Sciences, Bacterial Physiology, Pathogen, Multidisciplinary, Virulence, biology, Reverse Transcriptase Polymerase Chain Reaction, Host-Pathogen Interactions, Medicine, Pathogens, Cellular Structures and Organelles, Research Article, Pathogen Motility, Virulence Factors, Science, DNA transcription, Real-Time Polymerase Chain Reaction, Microbiology, 03 medical and health sciences, Microscopy, Electron, Transmission, Genetics, Humans, Operons, Type VI secretion system, Sequence Analysis, RNA, Mucin, Mucins, Biofilm, Biology and Life Sciences, Proteins, Bacteriology, DNA, Cell Biology, biology.organism_classification, Pili and Fimbriae, 030104 developmental biology, A549 Cells, Genes, Bacterial, Biofilms, Respiratory Infections, Transcriptome
Abstract: The capacity of Acinetobacter baumannii to persist and cause infections depends on its interaction with abiotic and biotic surfaces, including those found on medical devices and host mucosal surfaces. However, the extracellular stimuli affecting these interactions are poorly understood. Based on our previous observations, we hypothesized that mucin, a glycoprotein secreted by lung epithelial cells, particularly during respiratory infections, significantly alters A. baumannii's physiology and its interaction with the surrounding environment. Biofilm, virulence and growth assays showed that mucin enhances the interaction of A. baumannii ATCC 19606T with abiotic and biotic surfaces and its cytolytic activity against epithelial cells while serving as a nutrient source. The global effect of mucin on the physiology and virulence of this pathogen is supported by RNA-Seq data showing that its presence in a low nutrient medium results in the differential transcription of 427 predicted protein-coding genes. The reduced expression of ion acquisition genes and the increased transcription of genes coding for energy production together with the detection of mucin degradation indicate that this host glycoprotein is a nutrient source. The increased expression of genes coding for adherence and biofilm biogenesis on abiotic and biotic surfaces, the degradation of phenylacetic acid and the production of an active type VI secretion system further supports the role mucin plays in virulence. Taken together, our observations indicate that A. baumannii recognizes mucin as an environmental signal, which triggers a response cascade that allows this pathogen to acquire critical nutrients and promotes host-pathogen interactions that play a role in the pathogenesis of bacterial infections.
Published: 2018

48. Cryogenic Characterization of FBK RGB-HD SiPMs

Author: C. E. Aalseth, F. Acerbi, P. Agnes, I. F. M. Albuquerque, T. Alexander, A. Alici, A. K. Alton, P. Ampudia, P. Antonioli, S. Arcelli, R. Ardito, I. J. Arnquist, D. M. Asner, H. O. Back, G. Batignani, E. Bertoldo, S. Bettarini, M. G. Bisogni, V. Bocci, A. Bondar, G. Bonfini, W. Bonivento, M. Bossa, B. Bottino, R. Bunker, S. Bussino, A. Buzulutskov, M. Cadeddu, M. Cadoni, A. Caminata, N. Canci, A. Candela, C. Cantini, M. Caravati, M. Cariello, M. Carlini, M. Carpinelli, A. Castellani, S. Catalanotti, V. Cataudella, P. Cavalcante, R. Cereseto, Y. Chen, A. Chepurnov, A. Chiavassa, C. Cicalò, L. Cifarelli, M. Citterio, A. G. Cocco, M. Colocci, S. Corgiolu, G. Covone, P. Crivelli, I. D'Antone, M. D'Incecco, M. D. Da Rocha Rolo, M. Daniel, S. Davini, A. De Candia, S. De Cecco, M. De Deo, G. De Filippis, G. De Guido, G. De Rosa, G. Dellacasa, P. Demontis, A. V. Derbin, A. Devoto, F. Di Eusanio, G. Di Pietro, C. Dionisi, A. Dolgov, I. Dormia, S. Dussoni, A. Empl, A. Ferri, C. Filip, G. Fiorillo, K. Fomenko, D. Franco, G. E. Froudakis, F. Gabriele, A. Gabrieli, C. Galbiati, P. Garcia Abia, A. Gendotti, A. Ghisi, S. Giagu, G. Gibertoni, C. Giganti, M. Giorgi, G. K. Giovanetti, M. L. Gligan, A. Gola, O. Gorchakov, A. M. Goretti, F. Granato, M. Grassi, J. W. Grate, G. Y. Grigoriev, M. Gromov, M. Guan, M. B. B. Guerra, M. Guerzoni, M. Gulino, R. K. Haaland, B. Harrop, E. W. Hoppe, S. Horikawa, B. Hosseini, D. Hughes, P. Humble, E. V. Hungerford, An. Ianni, S. Jimenez Cabre, T. N. Johnson, K. Keeter, C. L. Kendziora, S. Kim, G. Koh, D. Korablev, G. Korga, A. Kubankin, R. Kugathasan, M. Kuss, X. Li, M. Lissia, G. U. Lodi, B. Loer, G. Longo, R. Lussana, L. Luzzi, Y. Ma, A. A. Machado, I. N. Machulin, L. Mais, A. Mandarano, L. Mapelli, M. Marcante, A. Margotti, S. M. Mari, M. Mariani, J. Maricic, M. Marinelli, D. Marras, C. J. Martoff, M. Mascia, A. Messina, P. D. Meyers, R. Milincic, A. Moggi, S. Moioli, S. Monasterio, J. Monroe, A. Monte, M. Morrocchi, W. Mu, V. N. Muratova, S. Murphy, P. Musico, R. Nania, J. Napolitano, A. Navrer Agasson, I. Nikulin, V. Nosov, A. O. Nozdrina, N. N. Nurakhov, A. Oleinik, V. Oleynikov, M. Orsini, F. Ortica, L. Pagani, M. Pallavicini, S. Palmas, L. Pandola, E. Pantic, E. Paoloni, G. Paternoster, V. Pavletcov, F. Pazzona, K. Pelczar, L. A. Pellegrini, N. Pelliccia, F. Perotti, R. Perruzza, C. Piemonte, F. Pilo, A. Pocar, D. Portaluppi, S. S. Poudel, D. A. Pugachev, H. Qian, B. Radics, F. Raffaelli, F. Ragusa, K. Randle, M. Razeti, A. Razeto, V. Regazzoni, C. Regenfus, B. Reinhold, A. L. Renshaw, M. Rescigno, Q. Riffard, A. Rivetti, A. Romani, L. Romero, B. Rossi, N. Rossi, A. Rubbia, D. Sablone, P. Salatino, O. Samoylov, W. Sands, M. Sant, R. Santorelli, C. Savarese, E. Scapparone, B. Schlitzer, G. Scioli, E. Sechi, E. Segreto, A. Seifert, D. A. Semenov, S. Serci, A. Shchagin, L. Shekhtman, E. Shemyakina, A. Sheshukov, M. Simeone, P. N. Singh, M. D. Skorokhvatov, O. Smirnov, G. Sobrero, A. Sokolov, A. Sotnikov, C. Stanford, G. B. Suffritti, Y. Suvorov, R. Tartaglia, G. Testera, A. Tonazzo, A. Tosi, P. Trinchese, E. V. Unzhakov, A. Vacca, M. Verducci, T. Viant, F. Villa, A. Vishneva, B. Vogelaar, M. Wada, J. Wahl, S. Walker, H. Wang, Y. Wang, A. W. Watson, S. Westerdale, J. Wilhelmi, R. Williams, M. M. Wojcik, S. Wu, X. Xiang, X. Xiao, C. Yang, Z. Ye, F. Zappa, G. Zappalà, C. Zhu, A. Zichichi, G. Zuzel, Aalseth, C. E., Acerbi, F., Agnes, P., Albuquerque, I. F. M., Alexander, T., Alici, A., Alton, A. K., Ampudia, P., Antonioli, P., Arcelli, S., Ardito, R., Arnquist, I. J., Asner, D. M., Back, H. O., Batignani, G., Bertoldo, E., Bettarini, S., Bisogni, M. G., Bocci, V., Bondar, A., Bonfini, G., Bonivento, W., Bossa, M., Bottino, B., Bunker, R., Bussino, S., Buzulutskov, A., Cadeddu, M., Cadoni, M., Caminata, A., Canci, N., Candela, A., Cantini, C., Caravati, M., Cariello, M., Carlini, M., Carpinelli, M., Castellani, A., Catalanotti, S., Cataudella, V., Cavalcante, P., Cereseto, R., Chen, Y., Chepurnov, A., Chiavassa, A., Cicalò, C., Cifarelli, L., Citterio, M., Cocco, A. G., Colocci, M., Corgiolu, S., Covone, G., Crivelli, P., D'Antone, I., D'Incecco, M., Rolo, M. D. Da Rocha, Daniel, M., Davini, S., Candia, A. De, Cecco, S. De, Deo, M. De, Filippis, G. De, De Guido, Giorgia, De Rosa, Gianfranca, Dellacasa, G., Demontis, P., Derbin, A. V., Devoto, A., Eusanio, F. Di, Pietro, G. Di, Dionisi, C., Dolgov, A., Dormia, I., Dussoni, S., Empl, A., Ferri, A., Filip, C., Fiorillo, G., Fomenko, K., Franco, D., Froudakis, G. E., Gabriele, F., Gabrieli, A., Galbiati, C., Abia, P. Garcia, Gendotti, A., Ghisi, A., Giagu, S., Gibertoni, G., Giganti, C., Giorgi, M., Giovanetti, G. K., Gligan, M. L., Gola, A., Gorchakov, O., Goretti, A. M., Granato, F., Grassi, M., Grate, J. W., Grigoriev, G. Y., Gromov, M., Guan, M., Guerra, M. B. B., Guerzoni, M., Gulino, M., Haaland, R. K., Harrop, B., Hoppe, E. W., Horikawa, S., Hosseini, B., Hughes, D., Humble, P., Hungerford, E. V., Ianni, An., Cabre, S. Jimenez, Johnson, T. N., Keeter, K., Kendziora, C. L., Kim, S., Koh, G., Korablev, D., Korga, G., Kubankin, A., Kugathasan, R., Kuss, M., Li, X., Lissia, M., Lodi, G. U., Loer, B., Longo, G., Lussana, R., Luzzi, L., Ma, Y., Machado, A. A., Machulin, I. N., Mais, L., Mandarano, A., Mapelli, L., Marcante, M., Margotti, A., Mari, S. M., Mariani, M., Maricic, J., Marinelli, M., Marras, D., Martoff, C. J., Mascia, M., Messina, A., Meyers, P. D., Milincic, R., Moggi, A., Moioli, S., Monasterio, S., Monroe, J., Monte, A., Morrocchi, M., Mu, W., Muratova, V. N., Murphy, S., Musico, P., Nania, R., Napolitano, J., Agasson, A. Navrer, Nikulin, I., Nosov, V., Nozdrina, A. O., Nurakhov, N. N., Oleinik, A., Oleynikov, V., Orsini, M., Ortica, F., Pagani, L., Pallavicini, M., Palmas, S., Pandola, L., Pantic, E., Paoloni, E., Paternoster, G., Pavletcov, V., Pazzona, F., Pelczar, K., Pellegrini, L. A., Pelliccia, N., Perotti, F., Perruzza, R., Piemonte, C., Pilo, F., Pocar, A., Portaluppi, D., Poudel, S. S., Pugachev, D. A., Qian, H., Radics, B., Raffaelli, F., Ragusa, F., Randle, K., Razeti, M., Razeto, A., Regazzoni, V., Regenfus, C., Reinhold, B., Renshaw, A. L., Rescigno, M., Riffard, Q., Rivetti, A., Romani, A., Romero, L., Rossi, B., Rossi, N., Rubbia, A., Sablone, D., Salatino, P., Samoylov, O., Sands, W., Sant, M., Santorelli, R., Savarese, C., Scapparone, E., Schlitzer, B., Scioli, G., Sechi, E., Segreto, E., Seifert, A., Semenov, D. A., Serci, S., Shchagin, A., Shekhtman, L., Shemyakina, E., Sheshukov, A., Simeone, M., Singh, P. N., Skorokhvatov, M. D., Smirnov, O., Sobrero, G., Sokolov, A., Sotnikov, A., Stanford, C., Suffritti, G. B., Suvorov, Y., Tartaglia, R., Testera, G., Tonazzo, A., Tosi, A., Trinchese, P., Unzhakov, E. V., Vacca, A., Verducci, M., Viant, T., Villa, F., Vishneva, A., Vogelaar, B., Wada, M., Wahl, J., Walker, S., Wang, H., Wang, Y., Watson, A. W., Westerdale, S., Wilhelmi, J., Williams, R., Wojcik, M. M., Wu, S., Xiang, X., Xiao, X., Yang, C., Ye, Z., Zappa, F., Zappalà, G., Zhu, C., Zichichi, A., Zuzel, G., AstroParticule et Cosmologie (APC (UMR_7164)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Physique Nucléaire et de Hautes Énergies (LPNHE (UMR_7585)), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), DarkSide, Aalseth, C, Acerbi, F, Agnes, P, Albuquerque, I, Alexander, T, Alici, A, Alton, A, Ampudia, P, Antonioli, P, Arcelli, S, Ardito, R, Arnquist, I, Asner, D, Back, H, Batignani, G, Bertoldo, E, Bettarini, S, Bisogni, M, Bocci, V, Bondar, A, Bonfini, G, Bonivento, W, Bossa, M, Bottino, B, Bunker, R, Bussino, S, Buzulutskov, A, Cadeddu, M, Cadoni, M, Caminata, A, Canci, N, Candela, A, Cantini, C, Caravati, M, Cariello, M, Carlini, M, Carpinelli, M, Castellani, A, Catalanotti, S, Cataudella, V, Cavalcante, P, Cereseto, R, Chen, Y, Chepurnov, A, Chiavassa, A, Cicalò, C, Cifarelli, L, Citterio, M, Cocco, A, Colocci, M, Corgiolu, S, Covone, G, Crivelli, P, D'Antone, I, D'Incecco, M, Rolo, M, Daniel, M, Davini, S, Candia, A, Cecco, S, Deo, M, Filippis, G, Guido, G, Rosa, G, Dellacasa, G, Demontis, P, Derbin, A, Devoto, A, Eusanio, F, Pietro, G, Dionisi, C, Dolgov, A, Dormia, I, Dussoni, S, Empl, A, Ferri, A, Filip, C, Fiorillo, G, Fomenko, K, Franco, D, Froudakis, G, Gabriele, F, Gabrieli, A, Galbiati, C, Abia, P, Gendotti, A, Ghisi, A, Giagu, S, Gibertoni, G, Giganti, C, Giorgi, M, Giovanetti, G, Gligan, M, Gola, A, Gorchakov, O, Goretti, A, Granato, F, Grassi, M, Grate, J, Grigoriev, G, Gromov, M, Guan, M, Guerra, M, Guerzoni, M, Gulino, M, Haaland, R, Harrop, B, Hoppe, E, Horikawa, S, Hosseini, B, Hughes, D, Humble, P, Hungerford, E, Ianni, A, Cabre, S, Johnson, T, Keeter, K, Kendziora, C, Kim, S, Koh, G, Korablev, D, Korga, G, Kubankin, A, Kugathasan, R, Kuss, M, Li, X, Lissia, M, Lodi, G, Loer, B, Longo, G, Lussana, R, Luzzi, L, Ma, Y, Machado, A, Machulin, I, Mais, L, Mandarano, A, Mapelli, L, Marcante, M, Margotti, A, Mari, S, Mariani, M, Maricic, J, Marinelli, M, Marras, D, Martoff, C, Mascia, M, Messina, A, Meyers, P, Milincic, R, Moggi, A, Moioli, S, Monasterio, S, Monroe, J, Monte, A, Morrocchi, M, Mu, W, Muratova, V, Murphy, S, Musico, P, Nania, R, Napolitano, J, Agasson, A, Nikulin, I, Nosov, V, Nozdrina, A, Nurakhov, N, Oleinik, A, Oleynikov, V, Orsini, M, Ortica, F, Pagani, L, Pallavicini, M, Palmas, S, Pandola, L, Pantic, E, Paoloni, E, Paternoster, G, Pavletcov, V, Pazzona, F, Pelczar, K, Pellegrini, L, Pelliccia, N, Perotti, F, Perruzza, R, Piemonte, C, Pilo, F, Pocar, A, Portaluppi, D, Poudel, S, Pugachev, D, Qian, H, Radics, B, Raffaelli, F, Ragusa, F, Randle, K, Razeti, M, Razeto, A, Regazzoni, V, Regenfus, C, Reinhold, B, Renshaw, A, Rescigno, M, Riffard, Q, Rivetti, A, Romani, A, Romero, L, Rossi, B, Rossi, N, Rubbia, A, Sablone, D, Salatino, P, Samoylov, O, Sands, W, Sant, M, Santorelli, R, Savarese, C, Scapparone, E, Schlitzer, B, Scioli, G, Sechi, E, Segreto, E, Seifert, A, Semenov, D, Serci, S, Shchagin, A, Shekhtman, L, Shemyakina, E, Sheshukov, A, Simeone, M, Singh, P, Skorokhvatov, M, Smirnov, O, Sobrero, G, Sokolov, A, Sotnikov, A, Stanford, C, Suffritti, G, Suvorov, Y, Tartaglia, R, Testera, G, Tonazzo, A, Tosi, A, Trinchese, P, Unzhakov, E, Vacca, A, Verducci, M, Viant, T, Villa, F, Vishneva, A, Vogelaar, B, Wada, M, Wahl, J, Walker, S, Wang, H, Wang, Y, Watson, A, Westerdale, S, Wilhelmi, J, Williams, R, Wojcik, M, Wu, S, Xiang, X, Xiao, X, Yang, C, Ye, Z, Zappa, F, Zappalà, G, Zhu, C, Zichichi, A, Zuzel, G, Bussino, Severino Angelo Maria, Da Rocha Rolo, M. D., De Candia, A., De Cecco, S., De Deo, M., De Filippis, G., De Guido, G., De Rosa, G., Di Eusanio, F., Di Pietro, G., Garcia Abia, P., Ianni, A. n., Jimenez Cabre, S., Mari, Stefano Maria, Navrer Agasson, A., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cicalã², C., G. De, Filippi, Guido, G. De, G. De, Rosa, and Zappalã , G.
Subjects: visible and IR photons, Physics - Instrumentation and Detectors, data acquisition, SiPMs, 1ST PROTOTYPES, 01 natural sciences, Photon detectors forUV, visible and IR photons (solid-state) (PIN diodes, APDs, Si-PMTs, G-APDs, CCDs, EBCCDs, EMCCDs etc), etc), Data acquisition, EMCCDs etc), APDs, Photon detectors for UV, visible and IR photons (solid-state), Instrumentation, Mathematical Physics, Physics, EBCCDs, Si-PMTs, Instrumentation and Detectors (physics.ins-det), Cryogenic detectors, Photon detectors for UV, visible and IR photons (solid-state), G-APDs, Physics - Instrumentation and Detector, performance, Dark current, noise, ionization: yield, Dark matter, quenching, High density, Cryogenic detector, FOS: Physical sciences, DarkSide, Noise (electronics), programming, Optics, 0103 physical sciences, Analysis software, photomultiplier: silicon, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], (solid-state) (PIN diodes, visible and IR photons (solid-state) (PIN diodes, 010306 general physics, SILICON, 010308 nuclear & particles physics, business.industry, CCDs, dark matter: detector, ITC-IRST, (solid-state) (PIN diodes, APDs, Si-PMTs, G-APDs, CCDs, EBCCDs, EMCCDs, time projection chamber: liquid argon, (solid-state), Photon detectors forUV, EMCCDs, RGB color model, business
Abstract: International audience; We report on the cryogenic characterization of Red Green Blue - High Density (RGB-HD) SiPMs developed at Fondazione Bruno Kessler (FBK) as part of the DarkSide program of dark matter searches with liquid argon time projection chambers. A cryogenic setup was used to operate the SiPMs at varying temperatures and a custom data acquisition system and analysis software were used to precisely characterize the primary dark noise, the correlated noise, and the gain of the devices. We demonstrate that FBK RGB-HD SiPMs with low quenching resistance (RGB-HD-LRq) can be operated from 40 K to 300 K with gains in the range 10(5) to 10(6) and noise rates at a level of around 1 Hz/mm(2).
Published: 2017
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49. Tissue Classification Using Optical Spectroscopy Accurately Differentiates Cancer and Chronic Pancreatitis

Author: Jeremy M. G. Taylor, Malavika Chandra, Barbara J. McKenna, James M. Scheiman, Seung Yup Lee, Oliver E. Lee, Robert H. Wilson, Diane M. Simeone, and Mary Ann Mycek
Subjects: Pathology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adenocarcinoma, 01 natural sciences, Article, 010309 optics, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Pancreatic cancer, Pancreatitis, Chronic, 0103 physical sciences, Internal Medicine, medicine, Humans, Pancreatitis, chronic, Pancreas, Principal Component Analysis, Hepatology, Receiver operating characteristic, business.industry, Spectrum Analysis, Cancer, Reproducibility of Results, medicine.disease, Pancreatic Neoplasms, medicine.anatomical_structure, ROC Curve, 030220 oncology & carcinogenesis, Pancreatitis, Radiology, Differential diagnosis, business
Abstract: Objectives Current pancreatic cancer diagnostics cannot reliably detect early disease or distinguish it from chronic pancreatitis. We test the hypothesis that optical spectroscopy can accurately differentiate cancer from chronic pancreatitis and normal pancreas. We developed and tested clinically compatible multimodal optical spectroscopy technology to measure reflectance and endogenous fluorescence from human pancreatic tissues. Methods Freshly excised pancreatic tissue specimens (39 normal, 34 chronic pancreatitis, 32 adenocarcinoma) from 18 patients were optically interrogated, with site-specific histopathology representing the criterion standard. A multinomial logistic model using principal component analysis and generalized estimating equations provided statistically rigorous tissue classification. Results Optical spectroscopy distinguished pancreatic cancer from normal pancreas and chronic pancreatitis (sensitivity, 91%; specificity, 82%; positive predictive value, 69%; negative predictive value, 95%; area under receiver operating characteristic curve, 0.89). Reflectance alone provided essentially the same classification accuracy as reflectance and fluorescence combined, suggesting that a rapid, low-cost, reduced-footprint, reflectance-based device could be deployed without notable loss of diagnostic power. Conclusions Our novel, clinically compatible, label-free optical diagnostic technology accurately characterizes pancreatic tissues. These data provide the scientific foundation demonstrating that optical spectroscopy can potentially improve diagnosis of pancreatic cancer and chronic pancreatitis.
Published: 2017

50. Quantitative Analysis of Single Amino Acid Variant Peptides Associated with Pancreatic Cancer in Serum by an Isobaric Labeling Quantitative Method

Author: Haidi Yin, Michelle A. Anderson, Mack T. Ruffin, David M. Lubman, Zhijing Tan, Song Nie, and Diane M. Simeone
Subjects: Nonsynonymous substitution, Adult, Male, Proteomics, Proteome, pancreatic cancer, Molecular Sequence Data, Mutation, Missense, Peptide, Single-nucleotide polymorphism, Enzyme-Linked Immunosorbent Assay, Biology, Biochemistry, Polymorphism, Single Nucleotide, Article, Young Adult, Tandem Mass Spectrometry, Pancreatic cancer, medicine, Biomarkers, Tumor, Humans, Amino Acid Sequence, Biomarker discovery, Peptide sequence, Aged, chemistry.chemical_classification, Aged, 80 and over, Reproducibility of Results, General Chemistry, Middle Aged, medicine.disease, Molecular biology, 3. Good health, Pancreatic Neoplasms, Isobaric labeling, single amino acid variant, chemistry, ROC Curve, Isotope Labeling, Biomarker (medicine), biomarker, Female, isobaric labeling, Peptides, serum, Chromatography, Liquid
Abstract: Single amino acid variations are highly associated with many human diseases. The direct detection of peptides containing single amino acid variants (SAAVs) derived from nonsynonymous single nucleotide polymorphisms (SNPs) in serum can provide unique opportunities for SAAV associated biomarker discovery. In the present study, an isobaric labeling quantitative strategy was applied to identify and quantify variant peptides in serum samples of pancreatic cancer patients and other benign controls. The largest number of SAAV peptides to date in serum including 96 unique variant peptides were quantified in this quantitative analysis, of which five variant peptides showed a statistically significant difference between pancreatic cancer and other controls (p-value < 0.05). Significant differences in the variant peptide SDNCEDTPEAGYFAVAVVK from serotransferrin were detected between pancreatic cancer and controls, which was further validated by selected reaction monitoring (SRM) analysis. The novel biomarker panel obtained by combining α-1-antichymotrypsin (AACT), Thrombospondin-1 (THBS1) and this variant peptide showed an excellent diagnostic performance in discriminating pancreatic cancer from healthy controls (AUC = 0.98) and chronic pancreatitis (AUC = 0.90). These results suggest that large-scale analysis of SAAV peptides in serum may provide a new direction for biomarker discovery research.
Published: 2014

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